Varicella-zoster virus (VZV), a double-stranded DNA virus belonging to the Herpesviridae family is a causative agent of two diseases in humans, varicella (chickenpox), usually during childhood, and herpes zoster (shingles), usually much later in adult life.
Respiratory mucosa is the portal of entry for most naturally acquired infections. The virus is then spread to regional lymph nodes, resulting in a primary viremic phase that carries the virus to the liver or other organs. Dissemination occurs via mononuclear cells. Replication in epidermal cells causes the typical varicella rash.
Primary VZV infection results invariably in the establishment of latent infection of cells in the dorsal root ganglia. Symptomatic VZV reactivation causes a localized infection, known as herpes zoster (HZ).
The main symptom of varicella and HZ is rash, accompanied by fever and malaise (varicella) or by radicular pain (HZ). Varicella lesions could cover the entire body; the HZ rash is mostly restricted to a single dermatome [World Health Organization, 2014]. Rash consists of pruritic erythematous macules which evolve through the papular stage to form clear, fluid-filled vesicles, superficially located in the dermis layer. Subsequent crusting of the lesions occurs 24–48 hours later. While the initial lesions are crusting, new crops form for about 5–7 days; the simultaneous presence of lesions in various stages of evolution is characteristic of varicella.
The main complications of varicella and, to a lesser extent, HZ, are secondary bacterial infections in children and varicella pneumonia in adults. Varicella, but not HZ, is dangerous for pregnant women for following reasons:
a) Varicella in pregnant women has less favourable course with frequent complications and increased mortality;
b) Varicella could cause both congenital and neonatal infections. Varicella embryopathy is characterized by microcephaly, limb hypoplasia, cutaneous defects, and damage to the autonomic nervous system.
The incubation period for varicella is 14 to 16 days, with a range of 10 to 21 days.
The virus is transmitted from person to person by direct contact with the varicella or HZ rash or (in contrast to other herpesviruses) by inhalation of aerosolized droplets from respiratory tract secretions of patients with varicella. Varicella is infectious from one to two days before the rash starts, and until all the blisters have crusted over (usually five to six days after the start of the rash). VZV could also be transmitted vertically: if a pregnant woman gets varicella in her 1st or early 2nd trimester, her baby has a risk (0.4 – 2.0 percent) of being born with congenital varicella syndrome. If the woman gets infected around time of delivery, the risk for infants is about 20% and the mortality rate is about 30%.
VZV is highly temperature sensitive, and it is readily inactivated by lipid solvents, detergents, and proteases.
The following patients are at risk for severe varicella with high mortality: immunocompromised, neonates, and pregnant females. Risk factors for HZ are age >50 years, immunosuppression, congenital or neonatal varicella.
Epidemiologically distinct VZV strains seem to exhibit very little antigenic variation, and no distinct subtypes of the virus have been identified. Recovery from primary varicella infection usually provides immunity for life.
VZV is found worldwide. In temperate climate and in the absence of a varicella vaccination programme, most people become infected by mid-adulthood, mostly during the first 5-10 years of life. In tropical regions infection is less prevalent and many people are infected during adulthood. Seroprevalence studies among young adults have demonstrated seronegative prevalences ranging from <5% in the USA to 14%–19% in Saudi Arabia, 26% in India and approximately 50% in Sri Lanka [World Health Organization, 2014].
Antibody production is usually detectable within 3 days after the onset of symptoms in healthy subjects.
Peak levels are attained at four to eight weeks. IgM antibodies decline within a few months while IgG and often IgA antibodies provide a long-term protection.
The temporal pattern of the appearance of antibodies following naturally acquired varicella and after immunization with VZV vaccine is generally similar. However, the magnitude of the vaccine- induced IgG antibody responses is consistently lower than that of responses observed after natural infection. There is good correlation between the strength of the antibody response after varicella vaccination and the protection seen after later exposure. A VZV glycoprotein (gp) antibody ELISA could be used as a correlate of protection, and evidence of seroconversion by that assay (concentration at 50-100 IU/ml is related to long-term protection).
Asymptomatic reinfections with concomitant increase in the level of IgG, IgM, and IgA play an important role in preservation of lifelong immunity. The response to HZ is of greater magnitude then that after asymptomatic reactivations and reinfections.
Lowest avidity antibodies are observed early after primary infection, while antibodies in sera taken from seropositive patients with no recent history of VZV disease or from patients with recent zoster show markedly higher avidity.
VZV DNA encodes at least 69 proteins. Primary VZV infection elicits IgG, IgM, and IgA antibodies that bind to many classes of viral proteins, the most important being viral surface glycoproteins, the major capside protein p155, and transcriptional regulator IE62. The linear sequence of many VZV genes is similar to that of herpes simplex virus type 1. VZV produces six glycoproteins. Antibodies to two major VZV structural glycoproteins, gB and gH, as well as to the VZV capsid protein (p 155) were detected shortly after the onset of varicella. Antibodies to these proteins persist for years. In contrast, antibodies to many other VZV glycoproteins and proteins appear later after primary disease, especially in immunocompromised individuals, and then disappear.
A clinical diagnosis of varicella and HZ could be based on the appearance and distribution of the vesicular lesions: for varicella, the lesions are localized on the trunk and extremities; for HZ, lesions are restricted to one dermatome. However, clinical diagnosis is becoming more challenging because fewer people get varicella and varicella in vaccinated people is often mild and atypical in presentatio. Therefore, laboratory confirmation of varicella is becoming increasingly important in routine clinical practice.
Laboratory confirmation of varicella or HZ is by detecting VZV DNA using PCR, isolating VZV in cell culture from vesicular fluid, saliva, cerebrospinal fluid or other specimens , and by measuring immune response.
Cell culture is not widely used because of the relatively prolonged time required to detect cytopathic changes. IFA and ELISA are sensitive and specific tests.
Despite the presence of false-positives due to elevated IgM under asymptomatic reinfections, positive IgM result from a person with a generalized rash is usually interpreted as laboratory confirmation of varicella. On the contrary, a single positive IgG ELISA result cannot be used to confirm a varicella case. Documentation of increases in IgG antibody titers requires collection of 2 specimens, making it unsuitable for diagnosing varicella disease during the acute varicella. IgG screening could be used to assess immunity or susceptibility to varicella which is important for groups at risk.
IgG avidity could be used to determine if a person who is IgG positive for VZV was infected with the virus in the past or more recently. Low avidity is an indicator for VZV primary infection.
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