Varicella-Zoster Virus Eye Disease
Thomas J. Liesegang
The varicella-zoster virus (VZV) is the etiologic agent of two common diseases: varicella (chickenpox) and herpes zoster (HZ). The biology and clinical course of the VZV infection have been intensively studied over the past two decades, spurred in part because of the AIDS epidemic. The host-VZV relationship appears to be complicated and dynamic. Endogenous reactivations of the virus are common, and rarely exogenous reinfections occur. These reactivations are often asymptomatic and may be detected only serologically. The cell-mediated immune response appears to be the main factor in viral containment and explains the severity and frequency of HZ infections in the elderly and in immunosuppressed patients. The lack of a complete animal model has hampered our investigation of the biology and therapeutic strategies directed against this virus.
Weller has recounted the progression of the medical knowledge about VZV.1 In 1875, Steiner demonstrated varicella to be an infectious disease by inoculating volunteers with vesicle fluid from an individual with varicella.2 Von Bokay noted the relationship between HZ and chickenpox in 1892, in that children exposed to individuals with HZ could develop chickenpox.3 Garland suggested in 1943 that HZ might be due to reactivation of VZV acquired earlier in life.4 In 1952, after 11 years of laboratory research, Weller and Stoddard succeeded in isolating and propagating VZV in vitro from vesicle fluid.5 Restriction endonuclease patterns of isolates from a patient with varicella and subsequent zoster showed that the viral genomes are identical.6 Unless epidemiologically related, VZV isolates differ slightly from one another; some variation also occurs after serial passage in vitro.6,7 The complete sequence of the VZV genome was determined in 1986,8 and the first genetically engineered VZV mutant was constructed in 1987.9 A versatile method for site-directed mutagenesis of the virus was performed using DNA cosmids to produce infectious virus in 1993.10 The varicella virus vaccine became available in the United States in 1995.
VIROLOGY
The VZV is one of eight herpesviruses that routinely infect humans. It is classified as human herpesvirus 3 and a member of the genus Varicellovirus, subfamily Alphaherpesvirinae, family Herpesviridae.11 Both VZV and herpes simplex virus (HSV) are subclassified as alphaherpes viruses, a group characterized by rapid growth and spread, destruction of infected cells, a variety of susceptible hosts, and the ability to establish latent infection primarily in ganglionic tissue (neurotropism).
Humans are the only natural host, and the virus grows fastidiously in primary or continuous human cell lines (including human diploid fibroblasts, embryonic lung fibroblasts, foreskin fibroblasts, and primary keratinocytes, as well as melanoma and schwannoma cells) and only poorly in nonhuman lines (guinea pig embryo and monkey kidney cells).12 The vesicle fluid from patients with both chickenpox and HZ induces similar distinct focal cytopathic changes in cultured cells.13 VZV is a cell-associated heat-labile virus that spreads from cell to cell by direct contact. VZV is not processed and released from cultured cells as efficiently as it is from cells in vivo, so the particle-to-infectivity ratio is quite high in cell cultures. The inability to produce high titers of cell-free virus has hampered studies of the biology and chemistry of the VZV.14
The varicella-zoster virion has a diameter of 150 to 200 nm, with a lipid envelope bearing the host cell membrane and glycoprotein spikes. The viral envelope aids in both attachment and penetration of the virus. The central core of the virus contains an icosahedral (5:3:2 symmetry) nucleocapsid composed of 162 capsomeres, within which is the viral genome. The amorphous protein-filled space between the nucleocapsid and the envelope is known as the tegument; it contains several proteins, including the immediate-early proteins and the late proteins. The specific antigenicity of the virus is conferred by the protein capsid and the glycoprotein peptomers; the host antibodies are formed against these antigens. Glycoproteins confer antigenicity through their incorporation into the viral external membrane; they are the primary contact point between the virus and the cell as infection is initiated. The glycoproteins of VZV have been examined in the greatest detail because these envelope proteins are essential to understanding the VZV-specific immunity and the production of improved vaccines.15
The virion attaches to cells by binding to heparan sulfate proteoglycans, followed by binding to a mannose-6-phosphate receptor.16 After attachment, viral glycoproteins fuse with cell membranes and the virion penetrates the cell. After penetration, the virion is uncoated and the nucleocapsid is transported to the nucleus; tegument proteins may also be transported to the nucleus, where they initiate transcription of viral genomes. Initially, the viral immediate-early genes are expressed, which activate expression of the viral early genes. The latter encode proteins important for replication of viral DNA (e.g., thymidine kinase, polymerase, major DNA-binding protein). Finally, the late viral proteins are expressed. These are structural proteins that compose the viral nucleocapsid, tegument, and envelope. Viral DNA is packaged into nucleocapsids and transported out of the nucleus, where it acquires a glycoprotein envelope (either from the nuclear membrane or cytoplasmic vacuoles), and then virions are released from the cell.12
The inability to produce high titers of cell-free virus has limited the ability to assign genes formally to individual kinetic classes in the replication cycle and to study viral DNA replication. We know little about the mechanism by which VZV establishes latency in the central nervous system (CNS) and the function of viral genes in this process. Even less is known about the pathways responsible for the reactivation of virus from latency.
The varicella zoster virion is among the smallest of the herpesvirus genomes. The double-stranded genome is linear in the virus particle but circularizes within the infected cell. The viral genome consists of a double-stranded linear DNA for approximately 125,000 base pairs,17 capable of encoding about 75 proteins,14 all but 5 of which have homologues with HSV-1. The genome is organized into two portions, a unique long region and a smaller unique short region. Each of these regions is surrounded by inverted repeat elements. During DNA replication, the unique short region and its repeat become inverted, producing two isomeric forms of VZV DNA.14 Each end of the viral genome contains a single unpaired nucleotide that can base pair to form a circular molecule during replication of the genome. Thus, approximately half of the molecules contain the unique short region in one orientation and half in the other. In contrast, HSV has two regions that become inverted and result in four isomeric forms. Individual virions of VZV contain one or the other isomer form, and the two forms are equally infectious. The genome contains five repeat elements that can be analyzed by restriction endonucleases, allowing a distinction between different strains of VZV.12 The viral DNA is integrated into the host’s cellular machinery; this aids in replication but also avoids immune surveillance and antiviral drug eradication.
The area controlling DNA replication in the VZV genome has been mapped to a 45-base pair palindrome in the short repeat region.18 This is homologous to corresponding regions of HSV, implying that the enzymes necessary for DNA replication in these viruses share similar properties.14 There are also several other regions with sequences similar to HSV; this has led to accurate predictions of localization of important viral genes based on the more advanced knowledge of the HSV genome.8 There are at least six glycoproteins in VZV, and all resemble HSV glycoproteins. These glycoproteins were originally termed gpI to gpVI but have now been reclassified to correspond to their HSV homologues: gE (gpI), gB (gpII), gH (gpIII), gI (gpIV), gC (gpV), and gL (gpVI). Because these glycoproteins are potent inducers of antibody, they may be suitable for incorporation into future subunit vaccines.14
Molecular studies, specifically restriction endonuclease analysis of viral DNA, confirmed that HZ is caused by reactivation of latent VZV initially causing varicella in the host.6 Different viral isolates show slight variations in the mobility of certain DNA fragments.19 Isolates from a single outbreak of varicella do not show differences in DNA mobility, implying that the genome structure is relatively stable.14 The small variability that exists between epidemiologically unrelated isolates arises most often from gains or losses in the number of small repeat elements in the DNA.14
EPIDEMIOLOGY OF VZV INFECTION
Although obvious now, intensive epidemiologic, immunologic, and biologic studies were necessary to confirm that varicella and HZ are different clinical conditions caused by the same virus.13
VARICELLA
Varicella (chickenpox) is a common childhood illness, with more than 90% of the population developing clinical or serologic infection by adolescence20 and almost 100% by age 60.21 Varicella is highly communicable, with an incubation period of approximately 14 days. The incidence of varicella in the United States approximates the annual birth rate. Varicella is spread by droplet or airborne transmission and is highly contagious. The virus infects the host through the conjunctiva and/or mucosa of the upper respiratory tract. Chickenpox can be acquired by contact with either varicella or HZ lesions or by respiratory inhalation. Patients are contagious for 2 days before onset of the rash and then until all lesions have crusted. Chickenpox generally confers lifelong protection against a subsequent attack, but second infections have been documented. Asymptomatic reinfection (documented by a rise in antibody titer) may occur after exposure to varicella.22 In immunosuppressed patients or in patients whose initial infection was mild or subclinical, symptomatic reinfection may occur.23
The epidemiology of varicella varies remarkably between temperate and tropical climates. In tropical areas, varicella typically occurs among older persons. The distinctive age distribution of varicella seen in tropical climates is agent-specific rather than attributable to nonspecific factors, such as absence of crowding indoors in the winter.24 Epidemiology studies done by Preblud20 in the late 1970s and early 1980s indicated that there was significant morbidity (bacterial infection, encephalitis, pneumonia) and death caused by varicella in healthy individuals. Epidemiologic studies by the Centers for Disease Control indicate that up to 10,000 hospitalizations and 100 deaths per year occur in the United States from complications of varicella infection.
HERPES ZOSTER
Herpes zoster occurs during the lifetime of 10% to 20% of all persons.14 The most striking feature of the epidemiology of HZ is the increase in incidence observed with increasing age. The incidence is approximately 131 per 100,000 person-years for the United States white population.25 The annual incidence of HZ ranges from only 0.4 to 1.6 cases per 1,000 otherwise healthy people younger than 20 years to 4.5 to 11 cases per 1,000 among those aged 80 years or older.25,26 The lifetime incidence of HZ among African-Americans appears to be only half that reported by whites.27 The great majority of dermatologic HZ cases results from reactivation of latent virus; there is an absence of any increase in HZ concurrent with epidemics of varicella.28 There are reports of small epidemics of HZ, suggesting that it could be exogenously acquired or reactivated, although these reports of acquisition can usually be explained by chance.29 Both silent reactivation (documented by a rise in antibody titer) and clinically apparent reinfection with a different VZV have been well documented.22,23
Herpes zoster can occur despite substantial antibody titer, so humoral antibody is not a major determinant.30 Children with immune deficiencies limited to defects in antibody synthesis do not develop severe or recurrent varicella or HZ. The known risk factors for developing HZ relate to the status of cell-mediated immunity (CMI) to VZV.24,25 Thus, the incidence of HZ increases with age (because VZV-specific CMI and CMI in general decline with aging), with immunosuppression (such as HIV), or immunosuppressive therapy, and after primary infection in utero or early infancy, when the normal immune response is decreased. In vitro measurement of lymphocytic response to VZV antigen shows a significant decline with advanced age, with development of lymphoproliferative malignancies, and with the initiation of immunosuppressive treatment.31 The increased risk of HZ among persons infected with HIV requires consideration of HIV infection in any patient with HZ who is younger than 45 years or is in a recognized risk group for AIDS.32 The appearance of HZ in HIV-infected individuals or in individuals with AIDS-related complex appears to predict an increased risk for subsequent development of AIDS.33
HZ is more likely to be severe and prolonged and to lead to dissemination in an immunosuppressed patient.34 Dissemination implies a viremia. A few vesicles outside the primary dermatome are common even in normal patients and do not signify clinically important dissemination. Significant dissemination in an immunosuppressed patient is more likely to be accompanied by visceral or neurologic infection, both of which substantially increase the morbidity and mortality of HZ infection. Immunosuppressed patients may have chronic prolonged infection with sustained periods of new lesion formation, a failure of existing lesions to heal in the absence of antiviral therapy, and persistent CNS infection with progressive encephalopathy.35
PATHOGENESIS OF VZV INFECTION
After primary infection, VZV enters the dorsal root and trigeminal ganglia, where it remains latent for the lifetime of the individual. The entire viral genome is present in the latently infected ganglia, and VZV is latent in multiple ganglia along the entire human neuraxis. Most dorsal root and cranial nerve ganglia from immune individuals contain detectable latent VZV (65% to 90% of trigeminal, 50% to 80% of thoracic, 70% of geniculate ganglia).36,37,38,39 The latent genome may persist in an episomal form similar to that of HSV.
The frequency of dermatomes involved in HZ corresponds to the centripetal distribution of the initial varicella lesions, suggesting that the latency arises from contiguous spread of the virus during varicella from infected skin cells to sensory nerve endings with subsequent ascent to the ganglia. An alternative explanation, however, is that the ganglia are infected hematogenously during the viremic phase of varicella and that the frequency of dermatome involvement in HZ reflects the ganglia most often exposed to reactivating stimuli.14 At autopsy, attempts to recover latent VZV in culture from previously infected ganglia have been unsuccessful,40 although the virus has been recovered when active VZV ganglion infection existed in the corresponding dermatome at the time of death.41,42
During varicella infection, the VZV replicates efficiently initially in both neural and non-neural (satellite) ganglion cells. The total amount of latent VZV is low; therefore, conventional methods to detect latent VZV have proved limited.43 Because the amount of latent VZV per cell is also very low, the question of which cell type is involved in VZV latency could not be conclusively settled by the use of traditional in situ hybridization studies. Investigators have demonstrated VZV by in situ hybridization in either neurons44 or non-neuronal satellite cells.45,46 By using a combination of in situ polymerase chain reaction (PCR) and in situ hybridization, latent VZV DNA has been identified in the nucleus of the neurons only43 or predominantly neurons.47
Although animal models of VZV infection are available, reactivation-associated disease does not occur in these systems. An in vitro system has been developed using human fetal ganglia and has shown that both neuronal and non-neuronal cells can support VZV growth, but that the virus can reactivate only from a combination of the two.11 Originally it was thought that this ability of VZV to reactivate in satellite cells, spread to other satellite cells, and infect neuronal cells might account for the more widespread and destructive ganglionitis seen with VZV as compared with HSV.
Only a very small percentage of ganglion cells (0.01% to 0.15%) exhibit VZV transcripts.46 Several VZV genes seem to be expressed during latency in the human trigeminal ganglia,48 although homologues of the HSV latency-associated transcripts have not been detected in VZV either during productive infection or during latency.12 Evidence for transcriptional activity of the latent genome consists of detection of gene products and at least five RNA transcripts.45,48 Mechanisms that limit transcription, maintain latency, or induce reactivation are unknown. The cellular factors that influence the switch of viral gene expression from latency to lytic infection are unclear but are likely to involve a dynamic interaction with the immune system that allows the expression of pivotal viral mediators of reactivation.
The immune response does not prevent reactivation totally; more likely, subclinical reactivations occur in both immunocompromised and immunocompetent patients49,50,51 throughout life, and VZV-specific CMI acts to limit the spread of VZV within the ganglion, limit subsequent spread antegrade to the skin, and limit viral replication within the cutaneous lesions of HZ. Increases in VZV-specific immunity in immunocompetent patients in the absence of HZ suggest that reactivation can be limited to a subclinical event.51
The small dose of infectious virus released with HZ is immediately contained by circulating antibody or CMI and may never be evident clinically on the skin or mucous membrane. Both endogenous reactivation and exogenous re-exposure caused by either an association with a patient with varicella or with HZ22,23,52 or by VZV vaccine are important mechanisms in maintaining enhanced T cells ready to respond to endogenous VZV reactivation.53 This potential for a boost in T-cell response to VZV persists in the elderly.54 VZV viremia in asymptomatic immunocompromised patients who subsequently have boosts in VZV immunity50 and healthy subjects who have boosts in VZV immunity after dermatomal pain without cutaneous symptoms (zoster sine herpete),55 and neurologic VZV-produced disease or systemic VZV-produced disease without rash are examples of contained episodes of HZ.56 They can be confirmed by boosts in T-cell response and also by peripheral blood mononuclear cells with incomplete VZV DNA.57 The capacity of the immune response to limit spread of the virus is a major determinant of the early and late morbidity of HZ, assuming that the acute pain of HZ and postherpetic neuralgia result from tissue destruction and neuronal changes in the ganglion.28
CLINICAL COURSE
Community-acquired chickenpox is primarily spread via the respiratory tract, with contagiousness during the last few days of the incubation period and for the first few days after the rash appears. The communicability of VZV from active skin lesions of HZ is also best explained by respiratory means (causing varicella in nonimmune patients), although the period of contagion is much shorter, probably about 2 days.58
PRIMARY INFECTION
Chickenpox infection generally follows a benign course in normal children. Complications are more common and severe in immunosuppressed patients, neonates, and adults. The major complications are bacterial infection of the skin, severe skin disease (in immunosuppressed persons), neurologic complications (encephalitis), and pneumonia.20,59 The first viremia of varicella occurs a few days after infection, during which time viral replication has occurred within a localized area near the site of infection (usually the oral mucosa). This first viremia spreads the virus through the human host, and further cycles of replication occur. About 1 week later, a second transitory viremia occurs as circulating mononuclear cells and T lymphocytes travel through the reticular endothelial system and become infected by VZV.
The melanocytes may be an intermediary cell substrate in the viral transit process from the capillary into the basal layer of the skin. The epidermal cells are eventually involved in a process that has been called balloon degeneration because of the formation of large multinucleated giant cells. The nuclei are clustered in the center of each polykaryocyte; many of the nuclei contain eosin-staining viral inclusions. As the cells degenerate in the virally infected foci within the epidermis, an exudate develops and separates the dying cells to form a space filled with fluid. The appearance of this vesicular rash heralds the end of the incubation period.58
Ocular complications of varicella include eyelid lesions, conjunctival vesicles, dendritic epithelial keratitis, stromal keratitis, neurotrophic keratopathy, iritis, internal ophthalmoplegia, extraocular muscle palsies, cataract, chorioretinitis, and optic neuritis.60 The congenital varicella syndrome results most frequently from exposure to varicella during the first or second trimester and may be associated with ocular abnormalities such as chorioretinitis, optic atrophy or hypoplasia, congenital cataract, microphthalmos, and Horner’s syndrome.61
RECURRENCE OF VZV
Patients with HZ have a prodrome of fever, malaise, headache, and dysesthesia for 1 to 4 days before the development of the cutaneous lesions. The exanthem consists of grouped vesicles usually involving one but occasionally up to three adjacent dermatomes. The vesicles become pustular and occasionally hemorrhagic, with evolution to crusts in 7 to 10 days. Occasionally an attack is aborted before skin lesions appear but can be confirmed serologically (zoster sine herpete).62 VZV reactivation in the immunosuppressed host is usually associated with a more extensive and severe local rash than in immunocompetent individuals and is often accompanied by cell-associated viremia.63 The virus can be transmitted during the viremia to distant cutaneous or extracutaneous sites in scattered foci in 17% to 35% of immunocompetent HZ patients. Hematogenous spread of virus probably accounts for the appearance of a few vesicles in skin areas remote from the affected dermatome.
Disseminated HZ is defined as more than 20 vesicles outside the primary and immediately adjacent dermatome. Severely immunocompromised patients with HZ have a risk of dissemination up to 40%. In 10% of these high-risk patients, cutaneous dissemination is followed by progressive visceral involvement, particularly of the lungs, liver, and brain.64,65 Visceral dissemination may also follow in some immunocompromised patients who have no signs of cutaneous HZ.66 It may occur and recur frequently in otherwise clinically disease-free HIV-infected patients.67 Chronic VZV reactivation may occur in severely immunocompromised patients, with persistent viral replication at skin sites and episodes of viremia lasting several months. Recurrent VZV lesions in patients with AIDS are characterized by epidermal hyperplasia and massive hyperkeratosis with multinucleated giant cells and necrotic acanthotic keratinocytes.68
There are diverse neurologic complications associated with HZ, including motor neuropathies of the cranial and peripheral nervous system, encephalitis, meningoencephalitis, myelitis, and Guillain-Barré syndrome.69 A unique cerebral vasculopathy with a mortality of approximately 25% has been recognized in which contralateral hemiparesis develops weeks to months after herpes zoster ophthalmicus (HZO).70 Angiographic and autopsy studies confirm a cerebral vasculopathy with thrombosis and a granulomatous vasculitis involving large and small arteries, arterioles, and venules.71 Immunofluorescence and electron microscopy studies demonstrate the virus in the smooth muscle cells of the vascular media but not in the endothelium.
Involvement of the ophthalmic division of the trigeminal nerve, HZO, is disproportionately frequent and severe. It was richly described by Hutchinson in 1865.72 The ophthalmic division of the trigeminal nerve, by way of the frontal, nasociliary, supraorbital, and supratrochlear branches, provides sensory innervation not only to the skin of the forehead, temple, palate, and the tip of the nose, but also to the eye. The frontal branch within the ophthalmic division of the fifth nerve is most commonly involved. Rarely, all three branches of the ophthalmic division are affected simultaneously; even rarer is the simultaneous involvement of the ophthalmic, maxillary, and mandibular branches of the trigeminal nerve.
The most serious consequences are evident when the nasociliary nerve of the ophthalmic division is involved; this often signifies intraocular involvement. Subsequently, 50% of patients with HZO develop ocular complications.73,74
There are diverse potential ocular complications of HZO because there are numerous pathogenic mechanisms of viral replication and spread and because there are varying contributions of vasculitis, neuritis, and the immunologic and host inflammatory granulomatous reactions to infection.73,75,76 A chronic persistence of ocular symptoms is observed in approximately 29% of affected patients77; rarely, enucleation is required (Table 1).78,79 The inflammatory reaction can occur in any portion of the eye or adnexal tissue. The pathogenesis of the varied ocular complications of HZO is not fully known, although histopathologic studies demonstrate significant perivascular and perineural inflammation in ocular tissues.78,79 VZV can be isolated from the eye during acute HZO but usually not in delayed or chronic ocular disease. The virus has also been recovered, however, from the delayed pseudodendrites.80
TABLE ONE. Forms and Incidence of Herpes Zoster Keratitis | ||||||||||||||||||||||||||
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The most common infectious or immune complications of HZO include cicatricial lid retraction or loss, paralytic ptosis, conjunctivitis, scleritis, episcleritis, keratitis, iridocyclitis, secondary glaucoma, cataract, Horner’s syndrome, Argyll-Robertson pupil, glaucoma, retinitis, choroiditis, optic neuritis, optic atrophy, retrobulbar neuritis, exophthalmos, extraocular muscle palsies, postherpetic neuralgia, and orbital apex and inflammatory syndromes (Table 2).73,74,81
TABLE TWO. Incidence of Complications of Herpes Zoster Ophthalmicus | ||||||||||||||||||||||
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HZO IN IMMUNOCOMPROMISED PATIENTS
In immunocompromised patients, VZV infections have long been a major complication. Immunosuppressed organ transplant recipients and immune-deficient patients with cancer, leukemia, and AIDS are all at increased risk of HZ. In those with solid tumors, the incidence is 1% to 3%, in those with nonHodgkin’s lymphoma 7% to 9%, and in those with Hodgkin’s disease 13% to 15%, of which up to 30% disseminate.82 Depending on the severity of impairment of CMI, cutaneous dissemination occurs in 6% to 26% of patients within 4 to 11 days after localized HZ appears; half of these patients will have ocular, visceral, or neurologic involvement. Because reactivation of VZV in immunocompetent individuals younger than 45 is uncommon, the presence of HZ in patients younger than 45 must alert the physician to the possible coexistence of HIV infection. In a prospective study of HZ patients younger than 45, 75% had HIV risk factors or altered T-cell subsets.83 The majority of HZO cases in HIV patients are characterized by severe and enduring cutaneous lesions, epithelial and stromal keratitis, and anterior uveitis.84 In a group of 19 HIV-HZO patients with a mean age of 28 years, 89% developed punctate keratitis and anterior stromal infiltrates, 53% had iritis, and 42% contracted postherpetic neuralgia.
VZV can also involve the posterior segment of the eye in immunocompromised patients, manifesting as distinct clinical patterns of disease. It has been established as one cause of acute retinal necrosis (ARN) syndrome and the etiologic agent of progressive outer retinal necrosis (PORN) syndrome.85,86,87 Retinitis develops either from reactivation of latent VZV that was previously acquired or during the course of primary infection. Visual consequences may be mild or severe, with retinal detachment a major feature. Medical and surgical management is only partially effective in preventing vision loss. The pathogenesis of the retinitis is poorly understood; the site of latency, the factors responsible for VZV reactivation, and the manner by which the virus gains access to the eye remain unclear.88 There are disparate clinical appearances of VZV retinal infection in ARN and PORN syndromes, probably reflecting the severely altered host immune defenses in those affected with PORN syndrome.89 ARN is usually seen in patients without AIDS.
The presence of peripheral retinal perivasculitis and sheathing was found to raise the index of suspicion greatly for coexisting HIV infection in HZO patients.90 In general, this category of patients with combined infection requires prolonged therapy for chronic morbidity of disease.91 Prolonged therapy promotes resistant virus, with the suggestion that aggressive treatment be given early and that long-term oral suppression should be avoided.92
In contradistinction to these studies was a report indicating a relatively low incidence and benign nature of the stromal keratitis, iritis, and postherpetic neuralgia in a cohort of patients with HIV infection, but an increase in chronic infectious dendritic keratitis, retinitis, and CNS disease, all probably consequences of active viral replication.93 The absence of some complications may reflect the absence of an effective immune response, because many of these complications are purported to be immune in etiology. Features of HZO in HIV patients include an increasingly lower age at onset, skin eruption in multiple dermatomes, ocular disease sine herpete, the PORN syndrome, chronic infectious dendrites, and serious neurologic disease.93
VZV-HOST IMMUNE INTERACTION
In 1965, Hope-Simpson94 first hypothesized that continued immunity to VZV is the result of intermittent re-emergence of the latent original chickenpox strain and/or subsequent contact with another exogenous VZV stain. Either strain induces a brief, usually subclinical, infection that augments the VZV-immune status of the host. Subsequent studies have supported this hypothesis and have identified various antibodies as markers for times and types of infection. Susceptible individuals have no antibodies to VZV at the time of exposure to virus unless passive antibodies, acquired transplacentally or by administration of immunoglobin or blood products, are present. The role of humoral antibody alone in the containment of primary infection is not clear. Specific antibody modifies varicella but does not prevent infection. Circulating antibodies to VZV antigens participate in antibody-dependent cellular cytotoxicity along with natural killer cells in varicella and HZ. Although low levels of antibody can be demonstrated for decades in normal and some immunosuppressed patients, the cellular responses, as assayed by skin test reactivity or lymphocyte transformation tests, are often at low or undetectable levels in the elderly or immunosuppressed.95,96
PRIMARY INFECTION
Despite the incubation period of 10 to 21 days after viral inoculation, serum antibodies to VZV are usually not detected until 1 to 3 days after the appearance of the varicella exanthem. Acute primary VZV infection in both healthy and immunocompromised persons is associated with the rapid induction of IgG, IgM, and IgA antibodies directed against several viral proteins; antibodies of all the immunoglobin classes appear simultaneously in most cases. The initial IgG antibodies appear to be specific for viral glycoprotein targets on both the envelope of the virus and the surface of infected cells and also against nucleocapsid protein. IgM is specific for polypeptides, and IgA is directed against three VZV-infected cell proteins.97 IgG, IgM, and IgA antibodies appear 2 to 5 days after the onset of varicella rash and reach maximum titer during the next 2 to 3 weeks. Thereafter, IgG titers decline but persist at low levels for many years, whereas IgA and IgM antibodies usually are not detectable 12 months after the illness.30,98,99 Subsequent household exposure to HZ or varicella results in no clinical disease or change in IgG levels, but IgA titers increased two to four times within 2 to 4 weeks before returning to baseline. This fluctuation in IgA titers indicated a subclinical reinfection. The initial IgG antibodies to VZV are predominantly in the IgG3 subclass.100 Neutralizing antibodies are predominantly IgM, but IgG antibodies have also been shown to neutralize the virus.101
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