Like the other members of the herpes virus family, VZV is an enveloped virus that contains double-stranded DNA within its protein core. The viral particle is an icosahedron, and the complete enveloped virion measures between 150 and 200 nm in diameter, while the naked particle is about 95 nm in diameter. The VZV genome contains approximately 125-kb pairs (21), with approximately 71 open reading frames. There is a geographic distribution of sequence variations of VZV, and these are grouped into clades (22,23). The VZV vaccine strain Oka is a clade 2 strain, and the ability to distinguish VZV outbreaks by clade type has become an important epidemiologic tool (24,25).

The CPE of VZV infection appears as syncytial cells with intranuclear inclusion bodies (13). In clinical disease, a similar inclusion body is observed in infected tissue, and, as noted, this CPE is identical for both chickenpox and HZ (15). Electron micrographic analysis of vesicle fluid from children with chickenpox demonstrates cell-free enveloped virions (17). It is presumed that VZV acquires an envelope by budding out of the nucleus and into a cytoplasmic Golgi vesicle (26). The membrane of these Golgi vesicles contains viral glycoproteins, and thus the virus obtains the surface glycoproteins to which the immune system will be targeted. The molecular aspects of VZV replication has been reviewed (27).

It is well recognized that iatrogenic or natural reduction in cellular immunity is associated with both severe varicella and increased reactivation of latent VZV (42, 43, 44, 45, 46 and 47). Cellular immunity to VZV has been classically measured by VZV-specific lymphocyte proliferation assays (48,49) and by quantitative measures of cytotoxic T lymphocytes (50,51). Susceptible individuals fail to have an in vitro response either to crude VZV antigens or to individual VZV protein, but those with prior history of chickenpox develop a cellmediated immune response to the individual VZV glycoproteins (48). Analyses suggest that VZV proteins gI (ORF68) and immediate-early protein 62 (IE62; ORF62) are important for induction of a protective immune response to VZV (50). Several methods for quantitative T-cell immune assays are available in research laboratories, as described (52, 53 and 54).

In healthy children, the clinical features of VZV infection present as a mild exanthema often associated with prodromal malaise, pharyngitis, and rhinitis, appearing at a median time of 15 days after exposure (55,56). The rash is characterized as a vesicular eruption that emerges in successive crops over the first 3 to 4 days of illness, usually with concomitant exanthema. Each skin vesicle appears on an erythematous base, thereby giving rise to the descriptive “dewdrop on a rose petal.” It can be difficult to see this stage of infection because of the rapid progression of the skin changes. A quick progression from stage to stage is characteristic of varicella in the otherwise healthy child and allows it to be distinguished from certain other vesicular eruptions and from varicella in the immunosuppressed person. Within 12 hours, the initial lesion becomes an umbilicated papule, and the crusted area then undergoes leukocyte infiltration and develops into a pustule. This then evolves into a hardened, crusted papule. The exanthema usually begins on the head, quickly progresses to the trunk and arms, and finally appears on the legs. Because of the rapid progression of individual lesions, it is common to see all stages of the exanthema, including macules, vesicles, papules, and crusts, in the same region of the skin. Fever can be expected to be elevated for the first 4 days of the exanthema, and much of the morbidity is associated with the extent of the cutaneous exanthema (55).

In 1900, Head and Campbell (57) described the anatomic pathology of this syndrome and its precise localization to sites of single dermatomes, which permitted a mapping of the cutaneous distribution of the spinal nerves. Immunosenescence (51) and stress (58) are associated with risk factors for HZ. The clinical morbidity of HZ is determined in large part by the spinal ganglion involved. The most common area of involvement is the trunk, presumably because this is the area of greatest VZV infection during the primary infection, followed by cranial dermatomes and then by cervical and lumbar dermatomes (57,59,60). The involvement of cranial nerves is usually associated with the most clinically severe syndromes.

The pain associated with this disease is usually its major complication, although motor incapacitation can also be significant in the symptom complex (61,62). The pain of HZ, called postherpetic neuralgia, occurs with increasing frequency in older persons and can be a significant problem, lasting for many months (59,63, 64 and 65). This is presumably due to the fact that virus reactivation occurs in the dorsal spinal ganglion, which becomes a site of intense inflammation, often with hemorrhagic necrosis of nerve cells and eventual destruction of portions of the ganglion and with poliomyelitis of posterior spinal columns and leptomeningitis (66). Certainly there is intense inflammation and nerve damage manifested clinically by meningitis and myelitis, with or without paresis of limbs, face, gut, or urinary bladder (64,66, 67, 68, 69, 70, 71 and 72) in some cases. Recently, the role of the IE62 of VZV, which is a major transactivator of viral genes, has been suggested as an activator of brainderived neurotrophic factor (BDNF). BDNF is involved in the pathogenesis of neuropathic pain, and antibody to IE62 augmented BDNF activity in neurons in an allodynia model in mice (73). If this is confirmed, the role of inflammation in pain induction during HZ could be mediated via IE62-specific VZV immune responses, and this could become an important target area for improving treatment of postherpetic neuralgia.

Prior to the licensure of VZV vaccine in the United States in March 1995, there were an estimated approximately 11,000 VZV-related hospitalizations annually in the United States, 80% of which occurred in otherwise healthy children, and approximately 100 deaths per year (74,75). The rate of complications was highest for persons <1 year old and >15 years old. Hospitalization rates relating to varicella, calculated from the Michigan Inpatient Database from 1983 to 1987, were 10 per 1,000 cases below age 1 year, 2 per 1,000 for ages 1 to 14 years, 5 per 1,000 for ages 15 to 19 years, and 8 per 1,000 for age 20 years and above. The types of complications that lead to hospitalization in VZV infection have been reviewed (74,76, 77 and 78) and consisted of bacterial superinfection of skin, dehydration, pneumonia, encephalitis, and hepatitis. Bacterial skin infections and bacterial pneumonias occur in the youngest groups; prior to the antibiotic era, severe bacterial infections, including osteomyelitis, were not uncommon in association with varicella. With the development of antibiotics, but prior to the recognition of an association between aspirin and Reye’s syndrome (79), the major fatal complications of VZV infection in childhood were encephalitis and Reye’s syndrome. Encephalitis occurred in approximately 1 in 11,000 cases in the age group 5 to 14 years and is described below. Reye’s syndrome was associated with varicella and formerly occurred at a rate as high as 1 in 6,600 cases in certain regions of the United States (80). With the reduction in occurrence of Reye’s syndrome after varicella, VZV-associated mortality decreased from an average of 106 deaths per year in 1973 to 1979, to 57 per year for the period 1982 to 1986 (81) and finally to 43 per year in 1990 to 1994 (82). This reduction also coincided with the prohibition of aspirin use in children with chickenpox and then with the availability of acyclovir and of varicella-zoster immune globulin (VZIG), and undoubtedly each contributed to this reduced mortality. The pre-VZV vaccine age-specific case-fatality ratios were reported as 6.23/100,000 at ages <1 year, 0.75/100,000 at ages 1 to 14 years, 2.72/100,000 at ages 15 to 19 years, and 25.2/100,000 for ages 30 to 49 years (81). Mortality rates in the postvaccine era have fallen dramatically (see “VZV Vaccine,” below).

Clusters of severe, occasionally fatal, group A streptococcal infection have historically been associated with varicella, and therefore aggressive management of bacterial infection is warranted (82,83). Although not usually considered a healthcare-associated infection, pyoderma, the most frequently observed bacterial complication of varicella (77,78), should be considered a healthcare-associated infection if it complicates the course of the hospitalized patient with VZV infection. This problem can be minimized by attention to good hygiene, including daily bathing with bacteriostatic soap, trimming of children’s fingernails to minimize excoriation of itchy skin, and early recognition and treatment of superinfection.

In addition to the occasional laryngitis and laryngotracheobronchitis that can occur during varicella, bacterial superinfection can also involve the lower respiratory tract, producing pneumonia and bronchitis. Treatment should be directed toward the usual respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus (78). Viral pneumonia is more likely to be a problem in older persons with varicella. In persons of ages 15 to 19 years, varicella-related pneumonia occurred in 1 in 3,000 cases, but in adults, clinically significant disease has been reported in 1 in 375 cases of varicella (80). Asymptomatic pulmonary disease with radiographic changes has been reported to occur in 16% of adults (84).

Varicella is a generalized infection involving all epithelial areas, including mucosal surfaces of respiratory, alimentary, and genitourinary systems. Involvement of the bladder and urethra can result in severe dysuria with functional bladder obstruction. Urinary analgesics and bladder drainage may be required.

When death occurs during VZV infection, the gastrointestinal system is often involved. Bleeding requires specific attention, particularly in the immunosuppressed subject. In addition, vomiting is not a usual part of the clinical course of this infection, and this symptom should alert the physician to look for abdominal or central nervous system (CNS) complications. As with other viral infections, surgical emergencies such as appendicitis and intussusception can occur during varicella. Mild hepatic involvement is seen in most children with varicella and is usually manifested by asymptomatic elevation of hepatic enzymes, for which no treatment is necessary (85). As noted above, Reye’s syndrome was described in association with varicella, often with concomitant use of aspirin in the child older than 5 years (79,86,87). Reye’s syndrome and other metabolic diseases must be excluded in any child with varicella in whom there is vomiting and changes in mental status (88).

VZV is trophic for epithelial tissue, and the CNS is not spared from this trophism, with encephalitis and myelitis appearing as important complications of VZV infection. It is important to note that with both varicella and HZ, neurologic disease can occur either before or after the acute infection (89,90) and can even occur with VZV reactivation in the absence of skin eruption, an entity called zoster sine herpete (91). Several CNS syndromes, including aseptic meningitis, polyneuropathy, myelitis, and encephalitis, have been observed in normal persons in association with otherwise occult VZV infection (92). VZV infection involving the CNS is of two types: cerebellar or cerebral complications during varicella and cranial or peripheral nerve complications during HZ. Cerebral complications present equally as either cerebral or cerebellar abnormalities, the latter being more benign (69,89,90). Cerebellar ataxia is the most common syndrome associated with varicella encephalitis in children and is generally a benign entity that is thought to be due to postinfectious demyelination (89,90,93). In older teenagers and adults, encephalitis occurred in approximately 1 in 3,000 cases of varicella (80). Rarer CNS syndromes, such as granulomatous angiitis and stroke-syndromes, have been observed following HZ,
but these are poorly understood syndromes that have not been etiologically related to reactivation of VZV. As with varicella, CNS disease in immunodeficient persons is an important problem in HZ, and progressive CNS disease can occur in persons with HIV infection (94, 95 and 96,97).

Bleeding disorders can occur during varicella and are due to disseminated intravascular coagulation, vasculitis, or idiopathic thrombocytopenic purpura. The syndrome of purpura fulminans must be treated with supportive therapy and with antibiotic therapy until bacterial sepsis is ruled out. Anaphylactoid purpura can follow an otherwise uncomplicated course of varicella and must be managed with appropriate attention to the status of renal function and the possibility of occult intra-abdominal hemorrhage. Idiopathic thrombocytopenic purpura can occur during active infection or during convalescence and usually responds to treatment with intravenously administered immune globulin (98).

The era of aggressive anticancer chemotherapy and acquired immunodeficiency syndrome has been associated with progressive VZV infection (4,5,94, 95 and 96,97,99,100). VZV infection in the immunosuppressed individual is associated with progression of infection from skin to internal organs. Severe skin eruption occurs with or without hemorrhage; there is high fever and spread of virus to visceral organs, producing hepatitis, pneumonitis, pancreatitis, small bowel obstruction, and encephalitis (100,101). A major manifestation of visceral dissemination in addition to fever is severe abdominal and/or back pain (101,102). In the preantiviral era, visceral dissemination occurred in 30% of children with chickenpox while on active cancer therapy (100). Pneumonitis occurred between 3 and 7 days after onset of chickenpox in 25% of such patients; without antiviral therapy, the overall mortality rate in such patients was approximately 7%. In the placebo-controlled trials of antiviral agents in similar patients, a fatal outcome occurred in 17% and visceral dissemination occurred in 52% of the placebo groups (103,104,105). In addition to viral dissemination, bacterial superinfection was a problem in these patients, and bacteremia accounted for significant morbidity during VZV dissemination (100).

The severity of HZ is less predictable in patients receiving immunosuppressive agents. Historically, VZV will reactivate in 35% to 50% of persons with Hodgkin’s disease, and those undergoing bone marrow transplantation during the first year of treatment (106,107) and persons undergoing other forms of chemotherapy are at increased risk for zoster (108,109). The rates have not changed with intensive anticancer chemotherapy, and antiviral therapy significantly reduces this morbidity (62). When used early in reactivation, acyclovir can usually eliminate mortality (104,110,111).

The events that lead to the clinical syndrome of chickenpox are thought to be similar to those that were first proposed by Fenner to explain an animal model of viral exanthem (112). In this schema, virus enters the host from an exogenous source and spreads locally to a site of initial augmentation and then, by a primary viremia, to a location of subsequent viral growth. After several days of replication, the virus then spreads by means of a second viremia to the skin and mucosal surfaces, where the exanthema and enanthema occur (112). The entire time course for such virus replication and spread varies from 10 to 21 days, the range observed for the incubation period of varicella (55,56,113). The existence of the primary viremia has not been documented, but the secondary viremia is well described (114). Virus spreads to endothelial cells of the skin and then infects the basal and deep malpighian layers of the epidermis. The role of T-cell tropism of VZV in the transmission of virus to skin and nerve ganglia has been proposed (115). In addition, the VZV glycoprotein E contains an N-terminal region important for binding to the insulin-degrading enzyme (IDE) of cells in skin and other organs and glycoprotein E/IDE could be the critical ligand— receptor necessary for spread to the skin (36,116). Once in the skin, ballooning degeneration of these cells occurs and local collection of extracellular edema results in unilocular and multilocular vesicles (2,12). In addition to swelling of infected cells, multinucleation occurs, forming the basis for the Tzanck assay, and condensation of viral proteins within the nuclei results in intranuclear inclusions.