The Varicella zoster virus (VZV) is a member of the alpha-herpes family (Arvin, 1996, Kempfa et al., 2007) that gives rise to, a primary and secondary infection; Varicella (chicken pox) and Zoster (HZV; shingles) (Whitley and Gnann, 1999, Gnann, 2002, Quinlivan et al., 2007). An average of 4 million cases of VZV are reported each year (Cohen et al., 1999). VZV is known to share similar characteristics with the herpes simplex viruses, both able to establish latency in sensory nerve ganglia during a primary infection (Biron and Elion, 1980, Pevenstein et al., 1999). Primary varicella infection usually occurs only once with viral particle remaining dormant in the dorsal root ganglia of the spinal cord (Gilden et al., 1992, Pevenstein et al., 1999, Anderson et al., 2009) . Like herpes simplex virus (HSV-1 and HSV-2), VZV can reactivate after years of dormancy, in the form of a secondary infection; zoster (Lungu et al., 1995, Pevenstein et al., 1999). Studies show that at least one third of the population would be effected by this secondary infection (Larbis et al., 2008, Zussman and Young, 2008), with 50% of people over the age of 80 having had at least on bout of HZV during their lifetime (Whitley and Gnann, 1999). An investigation by Arvin in 1996 found the virus to be extremely sensitive to high temperatures, becoming inactivated at 50-600 C and non-infectious if the envelope is disrupted.
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Since zoster is primarily a pain and rash based disease, numerous studies have looked into possible treatment and preventative strategies for both strains (Arvin, 1996, Whitley and Gnann, 1999). The main purpose of the current investigation is to examine in detailed the impacts of existing management procedures for both primary and secondary varicella infections through the exploration of the virus and how development of the antiviral agent; acyclovir and two live attenuated vaccines have helped to reduce the severity of the disease.
VZV - the virus
Pathogenesis of primary and secondary VZV infections
Varicella is a highly infectious disease caused by the varicella zoster virus (VZV), a large icosahedral, enveloped, double stranded linear DNA virus (Arvin, 1996, White, 1997, Abendroth et al., 2010). VZV is found to be the smallest member of the human herpesvirus family with a genome of around 125, 000 bp (Davison and Scott, 1986, Rahaus et al., 2004). At least 69 open reading frames have been observed for the virus (Davison and Scott, 1986, Arvin, 1996).
Replication of the virus is strongly cell associated, expressing viral proteins 4 - 10 hours after exposure (Arvin, 1996). The virus replicates in three phases; viral adsorption and entry, viral gene transcription and viral assembly (Abendroth et al., 2010). According to an investigation by Reichelt et al, 2009 the virus enters the cell via fission of virion envelope with the plasma membrane or via endocytosis. Once inside the cell, capsid and virion tegument proteins are transported to the nucleus(Reichelt et al., 2009). Transcription then occurs via the synthesis of viral proteins (Reichelt et al., 2009). The transcribed proteins are classified depending on what time they are expressed after the virus enters the cell; immediate- early, early or late (Cohen et al., 2007)
Varicella (chickenpox) infects the host via direct contact with infectious lesions or via aerosol pathway with the viral particles passing into mucosa and conjunctive of the upper respiratory tract (White, 1997, Kempfa et al., 2007). Over the next 2-3 days the virus starts to replicate in lymph nodes promoting an initial virema. Once replication has begun the virus disseminates throughout the body via the bloodstream into the skin and mucosa tract (Kempfa et al., 2007). 10-14 days after an initial infection, further replication occurs in the spleen and liver, giving rise to a second bout of viremia (White, 1997). This second bout of verimia promotes the onset of a characteristic vesicular rash(White, 1997).
Virions from the initial infection are stored in the dorsal root ganglia; a nodulate enclosing neuron cell bodies, located along the dorsal root of the spinal cord (Anderson et al. 2009, McCary, 2010; Torpy et al. 2011). The latent virions remain in a dormant state for years (Whitley and Gnann, 1999), quite often unnoticed. Reactivation can occur in the form of shingles; zoster (Weaver, 2007). It remains unclear as to why the virions go into a dormant state and why reactivation occurs, with only one third of the population affected (Reichelt et al., 2009) . A study by Whitley and Gnann (1999), suggests the reactivation process is due to a decrease in the body's cell- mediated immune response that specifically targets the varicella virus. Age is believed to be the primary cause (Whitley and Gnann, 1999).
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Upon reactivation, neurons from the latent virus travel within the bloodstream and along sensory roots and nerve cells in the spinal column to the skin (Anderson et al., 2009, McCary, 2010). As a consequence of colliding particles, a rash is formed along adjoining dermatomes (Wood et al., 1998, Torpy et al., 2011). Unlike chicken pox it is rare for the rash to occur in more than one place, as shingles is a unilateral disease, restricted to singular dermatomes (Wallace and Oxman, 1997, Sampathkumar et al., 2009).
Clinical manifestations of the Varicella zoster virus
Varicella zoster is diagnosed upon the appearance of a characteristic blistering vescular rash, elevated fever and flu like symptoms (Weaver, 2007, McCary, 2010). The distribution of lesion
Zoster causes a blistering red rash that travels along singular dermatomes (Wallace and Oxman, 1997, Sampathkumar et al., 2009, McCary, 2010), often causing sever bouts of pain (postherpetic neuralgia) along this area as a result of sensory nerve damage (Whitley and Gnann, 1999). Varicella is less specific with lesions (300 on average) spread across the entire body (White, 1997).
In zoster the rash consists of blistering lesions that originates as red macules (Sampathkumar et al, 2009). Within a period of 7-10 days these red macules transform into crusting vesicles (Sampathkumar et al. 2009). It is at this stage that the virus becomes non-infectious (Sampathkumar et al. 2009). It can take over 4 weeks before scabs heal completely (Whitley and Gnann, 1999), but a lot longer before the inflicted pain (postherpetic neuralgia) subsides (Bowsher, 1997).
It is natural for shingles patients to experience severe attacks of pain along these areas (postherpetic neuralgia), often before the appearance of the distinctive rash (Whitley and Gnann, 1999). As a result the infection can often be misdiagnosed as appendicitis, pleurisy and other neurological pain based conditions (McCary, 2010).
There is at present only one majorly effective way to diagnose the disease; a medical examination of the infected area(s) (Sampathkumar et al. 2009; McCary, 2010). Other tests can be performed if an uncharacteristic rash appears. The tests utilize extracted vesicular fluid from a lesion as a source of diagnostics, but the additional tests are rarely required (McCary, 2010). There is a limited amount of knowledge known in regards to the effectiveness of the tests. If required, some of the diagnostic tests include a PCR (polymerase chain reaction), a Tzanck smear, fluorescence microscopy and culture growths (McCary, 2010).
Like many viral diseases complications can occur. In the case of Herpes zoster most side effects are of a neurological or bacterial nature (Sampathkumar et al. 2009). Postherpetic neuralgia, Guillain- Barre syndrome, encephalitis, meningitis, depression, Staphylococcus aureus, retinitis and scaring are a few of the more common side effects (Sampathkumar et al. 2009).
Probably the more frequent and severe complication of the Herpes zoster virus is postherpetic neuralgia (PHN) (McCary, 2010), a type of neuropathic pain caused by sensory nerve damage (Sampathkumar et al. 2009). Allodynia is the term for the excruciating pain felt via patients at the slightest touch to the sensitive area (PHN) (Sampathkumar et al. 2009; Sakai et al. 2006). Postherpetic neuralgia can last for a period of 3months or longer after the rash has cleared (Bowsher, 1997). Studies have shown that 10-15% of people diagnosed with shingles will be effected by postherpetic neuralgia (Sampathkumar et al, 2009; McCary, 2010), and approximately 50% of those would be over the age of 60 without the administration of antiviral treatments (Kost and Strauss, 1996; Whitley and Gnann, 1999). Like shingles postherpetic neuralgia is a difficult condition to treat as there is no reliably pain relief medication on the market at present to effectively relieve the pain (Sampathkumar et al. 2009). A series of systematically administered medications are advised and often require more than one type (Sampathkumar et al, 2009). Opoids and topical agents such as; lidocaine patches tend to be prescribed (Sampathkumar et al. 2009). It is not unusual for patients to become depressed as a result of PHN due to a lack in ability to sleep and perform a number of everyday functions (depending on location), therefore it is common for antidepressants to be prescribed in conjunction (Sampathkumar et al, 2009).
Treatment and Prevention
The treatment of Varicella zoster has been under investigation for a number of years with a large focus on antiviral therapy, vaccinations and other preventative methods that have been shown to increase the healing process and elevate discomfort (Wagstaff et al., 1994, Whitley et al., 1996).
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Antiviral therapies - Acyclovir
Studies have shown antiviral drugs to reduce the burden, length and severity of VZV infections and its painful side effects, but are incapable of providing a successful cure for the disease (Biron and Elion, 1980). For an antiviral to be considered effective it needs to be able to reach the desired target, remain metabolically stable and restrict DNA replication of the virus without unsettling the host's cell function (Bean, 1992). Early antivirals including idoxuridine, trifluorothymidine and cytosine arabinoside tended to be unsuccessful at carrying out such tasks due to high toxicity levels (Biron and Elion, 1980, Bean, 1992). This however changed upon the development of acyclovir in the 1970' s (Bean, 1992). Research confirmed the success of acyclovir demonstrating that it has an inhibitory effect on viral replication (Biron and Elion, 1980). By terminating replication the drug provides a relatively successful treatment method by elevating painful side effects (Bean, 1992, Whitley et al., 1996). Administration of the drug can occur in several forms but the most common are via oral or intravenous methods (Höglund et al., 2001). Best results have been found if the drug is taken within the 72 hour window period (Bean, 1992, Wood et al., 1998). Intravenous acyclovir was found to be more efficient at inhibiting replication this is due to the greater serum content (Bean, 1992). However for this reason the oral drug is generally prescribed as it is less toxic with serum levels less than 50% of that used for the intravenous drug (Bean, 1992).
Oral Acyclovir is at present the more effective drug available for the management of chicken pox in both adult and children sufferers, with recommended doses of 800mg, 5 times a day for a period of 1 week (Schmid and Jumaan, 2010).
Whitley and Gnann, 1999 also promotes the success of two other oral antiviral medications; Famciclovir and Valacyclovir, claiming the two pro-drugs to be more favourable by patients (Cunningham et al., 2008). Both drugs have a high bioavailability rate, easily accessible and less frequent doses are required (Schmid and Jumaan, 2010). There are still debates as to which of the three is better.
Disadvantages with the use of antiviral agents in the management of both primary and recurrent infections include no long term treatment or protection against the disease, targeting the symptoms not the cause.
Since an antiviral agent provides only a short term resolution, other methods were explored to determine if a long term strategy was possible (Evans, 2010). This is where the administration of vaccines comes in. In 1974 the first Varicella related vaccine was developed using blood samples of a young boy infected with the primary Varicella virus (White, 1997, Evans, 2010). 70 children were given the vaccine within three days prior to exposure with Varicella, of which no reported progression of chickenpox was found in any of the vaccinated children (White, 1997). Concluding this the development and evolvement of Varicella based vaccines have changed the way the virus is treated (Erlich, 1997).
Varivax is a live attenuated vaccine based on the Oka strain of Varicella, established and licensed in 1995 (Evans, 2010) . The vaccine was generated to prevent reactivation of latent virions (Zussman and Young, 2008). A study by Schmid and Jumaan, 2010 showed the vaccine had an 80-85% success rate and a further 95% at averting a more severe disease. As chickenpox is mostly susceptible to school aged children and young adults the vaccine was designed specifically for that age group (Dwyer and Cunningham, 2002, Schmid and Jumaan, 2010). Over the years many debates have been based around the long term effectiveness of the disease and whether the live Oka strain in the vaccine will promote an early onset reactivation of the latent infection (White, 1997).
A clinical study by White, 1997 identified that 95% of children who were vaccinated during the investigation showed signs of humoral and cell mediated immunity that appeared to have lasted for at least 6 to 10 years proceeding administration of the vaccine. However the long term duration of immunity is still unidentified.
2006 led to the development of Zostervax; the first licensed vaccine for the treatment of Zoster infections (Zussman and Young, 2008, Evans, 2010). Zostervax, like varivax contains a live attenuated strain of the Varicella zoster virus (Sampathkumar, et al. 2010). Since its development studies have acknowledged the significant reduction in disease severity by approximately 61% after the vaccine was administered (Sampathkumar et al., 2009). However there was still 49% of patients aged 60 and over that still contracted the disease (Sampathkumar et al. 2009; Levin et al. 2010).
The vaccine's functionality lasts for about 4 years before a booster is required (Sampathkumar et al., 2009). It is advised that the Zostavax should be taken frequently by everyone over 60 regardless of prior history with the virus according to the Advisory Committee for Immunization Practices (Sampathkumar et al. 2009).
Other preventative methods
As both primary and latent Varicella infections are largely rash and pain based several conventional methods are advisable for the protection of both patient and susceptible hosts. Such preventative steps include the use of gloves during examinations of infected area, crusted postulates should be covered as direct contact to the seeping lesions may promote the primary infection and segregate all formites used via the sufferer as the virus can live on such surfaces for a short time ,(McCary, 2010).
Varicella zoster virus was found to be the smallest member of the herpesvirus family, giving rise to a primary (chickenpox) and reccurant (shingles) infection.
A large proportion of research carried out on the transmission of shingles has been based on the reactivation and the distribution of the awakened virions and to whom is more susceptible to the disease. There is however limited resources available that describes in full the primary cause of reactivation and its association to the immune system. It was identified that the occurrence of shingles is greater in people who are immunocompromised or are of a certain age as the immune system was found to weaken with age for this particular disease. Characteristic symptoms have been outlined as an aid for a clinical diagnostics. Several treatment and preventative strategies were utilized throughout the treatment of shingles with majority of research documenting on the administrations of antiviral medication and a preventative vaccination. There is a still difficulty associated with the treatment and prevention of shingles and its pain related complication thus future research would benefit from studies focusing on such strategies.