Varicella Zoster Virus (VZV)

Last updated: July 9 2009.

Introduction

The varicella zoster virus (VZV) is the cause of chickenpox (varicella), and shingles (herpes zoster). Varicella occurs as the primary infection, more commonly in childhood but can occur in adulthood. Herpes zoster is a result of reactivation of latent infection of nerve ganglia.

Incidence

VZV infection was quite common prior to the introduction of the vaccine in 1995. Incidence rates of 1,500 per 100,000 have been reported. Since the introduction of the vaccine, reported incidence rates have markedly decreased. Information on overall Australian incidence is limited; the highest incidence rates (in 2006) were in South Australia (48.9:100,000) and the Northern Territory (93.4:100,000).

Herpes zoster has an incidence of 5.2:100,000 in Australia. Similarly, the highest rates were in South Australia (40.2: 100,000) and Northern Territory (38.7:100,000).

Causes

The main route of VZV infection is airborne transmission. In addition, direct contact may also transmit the virus. Unfortunately, even without the characteristic skin problems, a patient can still produce and spread the virus. The prodrome of varicella (non-specific symptoms such as fever and general malaise) gives little clue as to the proceeding illness. As such, preventing transmission can be difficult.

People with obvious varicella are advised to remain at home to minimize spread of the virus. It is advised that patients not attend their usual occupation until a crust has formed over the initial lesions. Virus shedding is minimized once this has occurred.

Herpes zoster is a reactivation of latent VZV infection. The risk of reactivation increases with age. In addition, reactivation is associated with immune compromise. HIV infection, bone marrow disease, or immune-suppressing medications may all predispose to reactivation and severe complications. However, reactivation may also occur randomly with no discernible cause.

Symptoms

The incubation period of VZV is approximately 14 days, during which the patient may experience a number of non-specific symptoms such as:

• Fever
• General malaise
• Abdominal pain
• Headache

Following these symptoms, the characteristic skin lesions evolve, beginning with a macular rash, progressing to vesicles, which rupture and form crusts that eventually heal. These lesions occur throughout the body, but are more concentrated around the trunk than the limbs. While this pattern is suggestive of varicella, abnormal distributions may occur.

Herpes zoster presents with similar skin problems. The distribution however, is less diffuse, and confined to a smaller region. The typical prodromal symptoms of fever and general tiredness may or may not be evident. However, pain in the same distribution as the skin lesions is likely, and may last even after the lesions have healed.

Treatments

Treatment for VZV infection is generally not required. However, guanosine analogues (such as acyclovir) are available. These are generally used in certain cases such as in immunocompromised patients, or in patients in whom severe infection or complications have developed. Passive immunization is also available. Immunoglobulin (antibodies) against VZV is administered to patients who are at risk of developing serious complications. This immunoglobulin is pre-formed and thus works even for immunocompromised patients.

The mainstay of treatment for VZV infection is prevention. A live attenuated vaccine was introduced in 1995. This vaccine has markedly reduced the rate of varicella. In addition, complication and mortality rates have also decreased.

A similar vaccine is also available to prevent herpes zoster.

Introduction

Varicella zoster virus (VZV) infection results in chickenpox or varicella (primary infection), and may also be followed by herpes zoster (shingles), which is reactivation of the dormant virus within nerve ganglia. Varicella primarily occurs in childhood. The rate of infection is currently trending downwards with the introduction of a varicella zoster virus vaccine.

Prognosis of the primary infection is generally good except in some instances. Patients who acquire the infection in adulthood have a higher mortality risk. Patients who are immunocompromised are also at risk. A developing foetus may acquire congenital problems if a primary infection occurs during pregnancy. Neonatal infections may also result in chronic complications.

Epidemiology and prevalence

Prior to the introduction of the varicella zoster vaccine in America, the incidence was estimated to be approximately 1,500-1,600:100,000 (Marin et al., 2008). Where varicella was the principal problem, the hospitalization rate was 2.3-6.3: 100,000. The case-fatality rate was reported as 0.8 per 100,000 in children aged 1-4 years, and 21.3 per 100,000 in adults aged more than 20 years. A separate series reports a mortality rate of 9.22 per 100,000 consultations related to varicella (Rawson et al., 2001). However, adults accounted for 81% of deaths despite representing only 19% of consultations. The majority of primary infections occur in children. While adults are less likely to acquire varicella, adults who do acquire the infection have a higher mortality rate.

Current post-vaccine surveillance data is available from the Department of Health and Ageing (with the exception of the Australian Capital Territory, Victoria, and New South Wales). A total of 1,514 cases of varicella were reported in 2006. The highest incidence rates of varicella were 93.4:100,000 in the Northern Territory, and 48.9:100,000 in South Australia (Department of Health and Ageing, 2006). The highest incidence occurred in children aged 0-4 years (120:100,000). The overall Australian incidence was not available.

A total of 1,052 cases of herpes zoster were reported in the same year. The overall rate was 5.2:100,000. Similarly, the highest rates were in South Australia (40.2: 100,000) and Northern Territory (38.7:100,000) (Department of Health and Ageing, 2006).

Surveillance data prior to the introduction of the varicella vaccine in Australia is unavailable.

Clinical features

Diagnosis is based mainly on clinical features. Confirmation by serological methods is available.

Varicella: In the primary infection, constitutional symptoms such as fever, general malaise, headache, and abdominal pain develop (Arvin, 1996). This is followed by a pruritic papular rash which develops into vesicles. These vesicles subsequently ulcerate or burst, form hard crusts, and eventually heal. Ulcerated lesions are often painful. These lesions typically develop around the entire body, but are concentrated centrally on the trunk. Lymphadenopathy is also seen.

Complications of varicella include secondary bacterial infection, transient hepatitis, respiratory and neurological involvement, haemorrhagic complications, and nephritis. Congenital varicella syndrome may also occur. Patients with neurological complications may have cerebral signs, cerebellar signs, or a combination of both. Signs of meningitis such as photophobia, headache, and neck stiffness may also occur. Congenital varicella syndrome is characterized by microcephaly, limb hypoplasia, cutaneous defects, hypopigmented skin, and autonomic neuropathy (Arvin, 1996).

Herpes zoster: The skin lesions that occur in herpes zoster are similar to those in varicella. However, because reactivation of the virus typically occurs from one particular ganglion, the lesions occur in the distribution of a specific dermatome (Spear & Straus, 2007).

Complications of herpes zoster include postherpetic neuralgia, and neurological involvement. Approximately 9% of patient with herpes zoster develop postherpetic neuralgia (Arvin, 1996), which is characterized by pain persisting for long periods of time despite resolution of skin lesions. Only 0.2-0.5% of patients have neurological involvement; the majority recover without permanent impairment (Arvin, 1996).

Etiology and pathogenesis

VZV belongs to the family of herpesviruses and specifically the alphaherpesviruses (Spear & Straus, 2007). Their genome consists of double-stranded deoxyribonucleic acid (DNA) within an icosahedral nucleocapsid. The outermost layer is a lipid membrane. This confers a susceptibility to environmental factors such as heat, and detergents or solvents. Transmission between hosts usually occurs via inhalation of aerosols containing varicella zoster virus. Transmission via direct contact is less frequent but may also occur. VZV is hypothesized to be spread via leukocytes in the lymphatic system (Arvin, 1996). The virions first spread to local lymph nodes, where a primary viraemia occurs. The virus then infects other leukocytes and hepatocytes before producing a secondary viraemia to infect mucous membranes and skin epithelia. The time up to this point is considered to be the incubation period, which lasts approximately 14 days (Arvin, 1996). Infection of the skin epithelia results in the characteristic lesions seen in varicella. Transmission of the virus is actually possible before the onset of these lesions (Arvin, 1996). Following this, the virus forms a latent infection within nerve ganglia (Spear & Straus, 2007).

Viral replication occurs within host cells. The virus binds to proteins on the surface of cells which induces its entry into host cells; the receptors used by VZV to facilitate cellular entry have not been identified (Spear & Straus, 2007). The host’s cellular mechanisms are then utilized to reproduce new viruses (Spear & Straus, 2007).

Both humoral and cellular immunity is important in containing the infection. In immunocompromised patients, severe complications of VZV are more likely to occur.

Prevention

Individuals at high risk (e.g. pregnant women, immunocompromised individuals) should avoid patients with active disease. Children who acquired varicella should stay at home until the skin lesions have healed or crusted.

Vaccination

Active immunization:

A live-attenuated vaccine for the prevention of varicella is currently available. This vaccine works by mimicking a viral infection; the strain used is not as virulent, and does do not cause disease readily. The body is still able to recognize the foreign components of the virus, and develop an immune response and long term immunity against it.

In Australia, it is recommended that newborns receive the vaccine between the ages of 12-15 months, followed by a second immunization at 4-6 years. Older children and adults who have not received the vaccine and have not previously been infected are advised to obtain the vaccine, unless there is a specific contraindication. The vaccine is available for free in Australia for those who fit the eligibility criteria (Department of Health and Ageing, 2008):

• All children born on or after 1 May 2004 at 18 months of age
• A one year cohort of children aged between 10 and 13 years who have not received varicella vaccine and who have not had the disease – commencement date and specific age group varies between States and Territories

The vaccine has been reported by Seward et al. (2002) to reduce mortality rates in America from 2.7-4.2:100,000 to 0.6-1.5:100,000. Other authors also support the cost-effectives of providing vaccination during infancy (Scuffham et al., 1999).

Contraindications to the varicella vaccine include (Zimmerman, 1996):

• Immuno-compromised individuals
      - Patients with HIV infection
      - Patients undergoing immunosuppressive therapy (such as high dose corticosteroid)
      - Patients with congenital immune deficiencies
• Individuals with a history of anaphylaxis
• Pregnancy
• Untreated tuberculosis

A similar vaccine is also available for prevention of herpes zoster (reactivation of latent VZV). This vaccine is similar to the varicella vaccine, but has a higher dose of live virus. It has been shown to reduce reactivation of latent VZV (Holcomb & Weinberg, 2006). Where reactivation occurs, the rate of post-herpetic neuralgia was reduced. In addition to the contraindications listed above for the varicella vaccine, the herpes zoster vaccine should not be given to children as it has a higher viral load.

Passive immunization:

Administration of intravenous immunoglobulin against VZV is sometimes used for immunocompromised patients who have been exposed to VZV. Active immunization (i.e. live attenuated vaccine) is contraindicated in these cases as the patient would be unable to mount an adequate immune response, and may in fact develop an infection instead.

Treatment

Varicella does not normally require anti-viral treatment. However, treatment may be warranted in patients with more severe infection, or who are at risk of developing further complications such as patients who are immunocompromised or have pre-existing skin conditions such as atopic eczema (Therapeutic Guidelines Ltd., 2004).

Guanosine analogues are frequently used. Guanosine analogues such as acyclovir are activated via intracellular phosphorylation by viral proteins. Following activation, they are incorporated into mRNA chains. Because these analogues are incompatible with the transcription process, the mRNA production chain is terminated. The relatively high affinity of acyclovir and other related drug for viral DNA-polymerase minimizes toxicity to non-viral host cells.

Treatment of immunocompromised adults with varicella with acyclovir did not improve skin healing rates, but significantly reduced visceral complications (Balfour et al., 1983). Acyclovir 10mg/kg for 7-10 days has been recommended. Administration via intravenous route over eight hours is preferred (Therapeutic Guidelines Ltd., 2004). Passive immunization may also be of use.

Treatment is required for all patients with herpes zoster. The following regimens are recommended by Therapeutic Guidelines Ltd. (2004):

Prognosis

The mortality and morbidity rates of VZV infection have been significantly reduced since the introduction of the live attenuated vaccine in 1995. However, significant complications may still occur. Primary infection in adulthood holds a poorer prognosis than childhood infection. Higher mortality rates have been reported (Rawson, 2001). Data on the rate of severe complications is limited. A German study estimated severe complications to occur at 8.5 per 100,000 cases (Ziebold et al., 2001). Of 119 cases in the study, neurologic complications occurred in 73 children (61.3%), infectious complications occurred in 46 children (38.6%). Only eight patients reported long term complications; six due to infectious causes, and two due to neurologic complications (Ziebold et al., 2001). Immunocompromised patients have much poorer prognosis.

The rate of developing congenital varicella syndrome is low. In a cohort of 362 women (15 with herpes zoster, and 347 with primary VZV infection), only one case of definite congenital varicella and two foetal deaths were documented (Harger et al., 2002).

The incidence of herpes zoster increases with age. Incidence ranges from 4.2 per 1,000 person-years (age group 50-59) to 10.7 per 1,000 person-years (age group ?80) (Yawn et al., 2007). The most common complication of herpes zoster is associated pain and post-herpetic neuralgia. On average, 18% of patients may experience pain for more than 30 days. Again, this proportion increases with age Yawn et al., 2007). Other complications include ocular complications (4%), and neurological complications (3%). Less than 1% develop disseminated infection (Yawn et al., 2007).

References

• Arvin, A M (1996). 'Varicella-zoster virus'. Clinical microbiology reviews, 9(3), 361-381. Available online.[Accessed on 9/12/2008].
• Balfour, H H Jr, McMonigal, K A & Bean, B (1983). 'Acyclovir therapy of varicella-zoster virus infections in immunocompromised patients'. Journal of Antimicrobial Chemotherapy, 12(B), 169-179. Abstract available online [Accessed on 9/12/2008].
• Department of Health and Ageing (2006). Australia's notifiable diseases status, 2006: Annual report of the National Notifiable Diseases Surveillance System - Results: Vaccine preventable diseases. Communicable Diseases Intelligence, 3(2). Available online. [Accessed on 9/12/2008].
• Department of Health and Ageing (2008). Varicella (chickenpox) vaccination program - common questions & answers for providers [Online]. Available online. [Accessed on 9/12/2008].
• Harger, J H, et al. (2002). 'Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women.' Obstetrics & Gynecology, 100, 260-265. Available online. [Accessed on 9/12/2008].
• Holcomb, K & Weinberg, J M (2006). 'A novel vaccine (Zostavax) to prevent herpes zoster and postherpetic neuralgia'. Journal of Drugs in Dermatology, 5(9), 863-866. Abstract available online. [Accessed on 10/12/2008].
• Marin, M, Meissner, H C & Seward, J F (2008). 'Varicella prevention in the United States: A review of successes and challenges'. Pediatrics, 122(3), 744-751. Available online. [Accessed on 9/12/2008].
• Rawson, H, Crampin, A & Noah, N (2001). 'Deaths from chickenpox in England and Wales 1995-7: Analysis of routine mortality data.' British Medical Journal, 323, 1091-1093. Abstract available online. [Accessed on 9/11/2008].
• Scuffham, P A, Lowin, A V & Burgess, M A (1999). 'The cost-effectiveness of varicella vaccine programs for Australia'. Vaccine, 18(5-6), 407-415. Abstract available online [Accessed on 9/12/2008].
• Seward, J F, Watson, B M, Peterson, C L, Mascola, L, Pelosi, J W & Zhang, J X (2002). 'Varicella disease after introduction of varicella vaccine in the United States, 1995-2000'. Journal of the American Medical Association, 287(5), 606-611. Abstract available online. [Accessed on 9/11/2008].
• Spear, P G & Straus, S E (2007). 'Alphaherpesviruses: Herpex simple virus and varicella-zoster virus'. Schaecter’s Mechanisms of Microbial Disease. 406-414. Lippincott Williams & Wilkins.
• Therapeutic Guidelines Ltd. (2004). Infectious diseases. Therapeutic Guidelines: Dermatology 2nd Edition. 201-220. Therapeutic Guidelines Limited.
• Yawn, B P, Saddier, P, Wollan, P C, StSauver, J L, Kurland, M J & Sy, L S (2007). 'A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction'. Mayo Clinic Proceedings, 82, 1341-1349. Available online. [Accessed on 10/12/2008]
• Ziebold, C, von Kries, R, Lang, R, Weigl, J & Schmitt, H J (2001). 'Severe complications of varicella in previously healthy children in Germany: A 1-year survey'. Pediatrics, 108(5), e79. Available online. [Accessed on 10/12/2008]
• Zimmerman, R K (1996). 'Varicella vaccine: Rationale and indications for use'. American Family Physician [Online]. Available online. [Accessed on 10/12/2008].

Online resources:

American Society of Health-System Pharmacists:

• Varicella vaccine information
• Herpes zoster vaccine information

Better Health Channel, Victoria:

• Varicella vaccine information
• Herpes zoster vaccine information
• Frequently asked questions and information on the varicella vaccine

Online associations:

• Australian Herpes Management Forum - The AHMF provides information for both patients and health professionals. Fact sheets are available for patients with information regarding herpes simplex virus as well as varicella zoster virus (chickenpox). Treatment and management guidelines are available for health professionals.
• International Herpes Management Forum
• Herpes Viruses Association