Heberden distinguished varicella and herpes zoster in 1867 but as smallpox has been eradicated so its differenciation from varicella is of historical interest only.Von Bokay suggested the infectious etiology and the predicted pathogenic relationship between the causative agents of varicella and herpes zoster in 1892.he made the observation based on the basis of the occurance of varicella in children after household contact with herpes zoster(46).varicella easthen frequently observed when the susceptible childrens were inoculated with the vesicular fluid recovered from the herpes zoster lesions.the secondary transmission resulted in typical varicella(323).The cutaneous lesions of varicella & herpes zoster were very similar in the in the early histopathological studies(78,211).The elementary bodies of the vesicular fluids differed from those of small pox vesicles but it suggested that the causative agent was a virus(7) and the virions from the varicella and the herpes zoster were found identical in electron microscopy(5).the first isolation of VZV in tissue culture was reported by weller and Stoddard in 1953.(366).Focal cytopathic effects and virion morphology couldnot be distinguished in cells inoculated with vesicular fluid recovered from cutaneous lesions of patients with varicella zoster.comparable antigenic profiles were registered using the immune sera(211).VZV was first classified as DNA virus because in tissue culture when iododeoxyurine was provided its replication was inhibited.(281).Restriction enzyme analysis of VZV DNa from sample virus isolated from an immmunocompromised patient during varicella and herpes zoster stated that herpes zoster resulted from the reactivation of the same vzv strain(325).
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Recent achievements include the sequencing of the complete VZV genome and production of the infectious virus from cosmids(71,87,235). VZV is the first human herpes virus for which a vaccine has been developed(134,330,335).live and attenuated vaccines protects susceptible indivusuals against primary VZV infections and has been accepted as a standard immunization in united states.
IMMUNE EVASION DURING THE LATENT INFECTION:
The mechanism by which the viruses defend itself from the immune system depends on the cells by which they establish a latent infection.
Current knowledge of the herpe s virus suggested that the virus establish latency in those stage which are a part of the immune system.it establishes direct modification of the host immune response by the virus.
Latent infection reflects a complex interaction between the virus and the host cell which remains unique for each virus and is charecterised by the (A).nature of cell harbouring the virus and (B).Viral gene expression in the cell harbouring the latent virus.
The host cell helps in determining the relationship between the virus with the host defence mechanism. Secondly the extent and the nature of the gene expression is a second key parameter ony because a latent virus must either restrict virus gene expression ,thus remaining antigenically silent or it silences the exposure of its presentation of the antigenic peptide structure to its host cell to avoid attack.
The human members of the Alpha herpesvirinae subfamily of the herpesviridae family ar herpes simplex virus 1 &2 and Varicella zoster virus(VZV).these viruses are considered as neurotropic and can infect nerve endings and can be transported by retrograde axonal flow to the neuronic nuclei where they can establish latency(3;4).These viruses have an extremely limited gene expression which helps it in avoiding recognition by the immune system.even in this viruses no protein products have not been detected in cells infective with these viruses. These viruses express very little or no MHC class 1 molequle and MHC class 2 antigens which limits the possibility of recognition by immune system.apart from these similar properties these viruses are significantly different in in the biology of latency.the latency of VZV will be described later.
LATENT HSV-1,HSV-2 & VZV INFECTIONS:
The alpha herpes virus HSV-1 & HSV-2 and VZV infects and infcts and replicates on the epithelial cells of the mucosal membrance and subsequently enter the neuronal cells of sensory gangilla that invervate the peripheral sites of infection(3).
A fraction of the neurons undergo the productive infection and perishes.in majority of the infected neuron genes expression conductive to the productive infection is suppressed.the viral genome than circularizes itself to form episome.the mechanism by which the virus attains latency are suppressed.it was thought that the neuron specific factors were necessary for this process.during the latent phase the virus exhibits very limited gene expression.The viral gene product detected during the latency were just a set of RNA transcripts known as latency associated transcripts or LATââ‚¬â„¢s.the largest but least abundant LATââ‚¬â„¢S is 8.5kb RNA.These are stable introns that accumulate in the nuclei and donot encode proteins(3).reactivation of this HSV 1 & 2 occurs periodically as a result of variety of stimuli including stress ,exposure to ultraviolet light, hormonal fluctuations etc.a progeny of viral infection ensues that the progeny of viral infections are transported by anterogade flow to a site or near the site of the neuron infection and ultimately the neuron gets destroyed as much by the immune system(3).The process occurs in such a way that the progeny of the reactivated virus itself populate new neuron cells and thereby insure feequent reactivation of the virus.
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PATHOGENESIS AND PATHOLOGY OF VARICELLA ZOSTER;
ENTRY OF VIRUS IN HOST:
Primary VZV infection is initiated by inoculation of the mucous membranes of the respiratory tract, with infectious virus transferred in respiratory droplets or by contact with infectious vesicular fluid from an infected individual
(149). However, documentation of the inoculation stage of VZV pathogenesis by isolation of infectious virus from respiratory sites has not been accomplished.
SITE OF PRIMARY REPLICATION AND VIRAL SPREAD:
Infectious agents of VZV moves to the lymph nodes after inoculation of the virus to the mucous membrance and undergoes a phase of replication into this site.after this phase a primary viremia is caused after which the virus is transported into the liver and other cells of the endoplasmic reticulum.this stages occur at an incubation period of 10 to 21 days.a secondary viremia occurs after the primary infection in the last 4 to 5 days of the incubation period or during the first 24 hours of acutre varicella.(25,206,234,260,344).in the secondary viremic phase it allows the desemination of the virus into cutaneous epithelial cells . Cell-associated viremia continues after the initial skin lesions develop, as shown by the recovery of VZV
from 11% to 24% of PBMC samples taken within 24 hours after the emergence of the varicella exanthem and its detection by in situ hybridization or PCR in 67% to 74% of otherwise healthy individuals who were tested immediately after the appearance of the rash ( 206,302).
During the late incubation period VZV also must be transported back to the respiratory mucosal sites because it gets transmitted to the susceptible contacts which are exposed within 24 to 48 hours before the appearance of the cutaneous lesions.infectious virus has rarely been recovered from the nasopharyngeal secretions during the preeruptive phase and was found in only 4.2% children with acute varicella.viral DNA has also been detected by PCR in the oropharyngeal specimens obtained before and after the appearance of cutaneous rashes(302).
CELLULAR AND TISSUE TROPISM:
The important cellular tropisms of VZV during the primary infections include T lymphoctytes ,skin cells, and cells of the dorsal root ganglia. Although the T-lymphocyte tropism is a necessary component of primary VZV infection, the site where T
lymphocytes become infected and the molecular mechanisms by which virus entry occurs have not been defined yet. After
the virus has been transported to skin during primary VZV infection, the cells of the epidermis become the major target
cells for further replication ( Fig. 5; Fig. 2). The virus may gain access to cutaneous epithelial cells by migration of intact, infected T lymphocytes out of the capillaries into cutaneous tissue, followed by release of virions ( 245). Infectious virus may move from T lymphocytes into endothelial cells forming the capillary walls, followed by
replication and spread to adjacent epithelial cells. Viral inclusions and viral proteins have been observed in capillary endothelial cells and in adjacent fibroblasts as well as in epithelial cells from VZV lesion biopsies ( 9,255). The lymphatics
of the superficial dermis are involved in the cutaneous infection, showing dilated lining cells with intranuclear inclusions(220). The pathogenesis of the characteristic varicella lesion was described by Tyzzer in 1906 ( 340), who noted that the
first changes consisted of vasculitis involving the endothelium of small blood vessels and that enlarged, multinucleated
epithelial cells with intranuclear eosinophilic inclusions were typical of the second, maculopapular stage of the lesions. These intranuclear inclusions are identical to those that appear in tissue culture cells during VZV replication, indicating
direct viral infection of the affected cell type. Progressive ââ‚¬Å“ballooningââ‚¬Â degeneration of epithelial cells associated with
formation of multinucleated cells, coalescence of fluid-filled vacuoles between cells, and increased numbers of infected
cells at the base of the lesion are noted as the maculopapular lesions evolve into vesicles; destruction of the germinal
layer of the epithelium is observed in larger lesions ( 131,220) (Fig. 6).
Events in the initial stages of primary VZV infection occur with little or no sensitization of the host immune system, as measured by antibody or T-cell responses to VZV antigens.
Infiltration of the involved skin sites by inflammatory cells is
minimal in the early vesicular phase. Later, cutaneous lesions progress to ulceration and are characterized by necrosis
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into the dermis. Using electron microscopy, virions can be seen in the capillary endothelial cells of varicella lesions, in
the keratinocytes of the epidermis, and as cell-free virus in vesicular fluid. Extensive aggregates of virus particles,including complete and hollow capsids, are visible in the nuclei of some keratinocytes ( 220).
Virions are also detectrd in the lysosomal components of macrophages within late stage lesions .in the skin biopsy specimens are analysed by immunohistochemical or in situ hybridization methods
Lung cells are the most important secondary
target of VZV from a clinical perspective because pneumonia is the most common complication of varicella and has a
high mortality rate. The pathologic changes of varicella pneumonia are associated with active infection of the epithelial
cells of the pulmonary alveoli (13). Infection induces mononuclear cell infiltration of the alveolar septa and edema of
alveolar septal cells, along with the accumulation of exudate, formation of hyaline membranes, and desquamation of
alveolar cells in the alveolar spaces. Desquamated septal cells in the alveoli and bronchiolar epithelial cells contain eosinophilic intranuclear inclusions, and dense patterns of virions are visible in these cells by electron microscopy.
PATHOGENESIS OF VARICELLA ZOSTER INFECTION: