Photomedicine

Herpes Simplex Virus (HSV)

Snapshot
Other common terms: Cold sores, herpes, genital herpes, HSV
ICD-10 classification: A60, >B00, P35.2
Prevalence: HSV1 56-76% of general population, HSV2 23-33% of general population
Causes: Direct contact infection; genital herpes (HSV2) is a sexually transmitted infection (STI)
Symptoms: Fluid-filled blisters on and around the site of infection.
Treatments/cures: Cannot be cured. Treatment with guanosine analogues is common.

Introduction

Herpes Simplex Virus under microscope
Herpes Simplex Virus magnified
Herpes simplex virus (HSV) infection (called cold sores and genital herpes depending on the site of infection) is a common infection which results from contact with persons or hosts who have the infection. Whilst HSV infections generally have good prognosis, important complications may occur, particularly with immunocompromised patients or neonates.

Incidence

Herpes is quite common in the community. Unfortunately, as cold sores and genital herpes are not a notifiable diseases, epidemiological data is limited. The virus can be acquired from a very young age. The rate of HSV infection rises with age, and eventually, most people would have been exposed. Figures between 56-76% of the population (see below) have been reported to have been infected by HSV1. The prevalence of HSV2 is much lower (23-33%), and is mostly associated with increasing sexual activity. Thus the incidence increases with older age, particularly with a higher number of lifetime sexual partners. Other rarer complications may result from HSV infection. These usually occur in immunesuppressed patients. Possible complications include herpes simplex keratitis, and herpex simplex encephalitis. Permanent damage my result including, visual impairment, and cognitive or neurological impairment. Neonatal infections are rare (reported as 3.9 in 100,000 live births). However, the mortality rate is relatively high (24%), and long-term sequelae may occur.

Known incidence studies on HSV infection

An Australian survey found 76% of 4000 participants to be seropositive for HSV1, and 12% of participants to be seropositive for HSV2. Similar results have been published in American studies. Siegel et al. (1992) reported on a community-based survey with sample size of 1212 individuals. Of these participants, 62% were seropositive for HSV1 and 33% were positive for HSV2. A higher prevalence rate was associated with increased age, and less education (for both HSV1 and HSV2). In addition, a higher rate of HSV2 infection correlated with being female, and the number of lifetime sexual partners. A similar study at a family medicine clinic found 56% of patients seropositive for HSV1, and 23% seropositive for HSV2. In summary, the majority of the population would have been exposed to HSV.

Causes

While genital herpes is considered to be a sexually transmitted infection, any form of contact is a possible route of infection. For example direct contact, and even through shared items. Unfortunately, due to the high prevalence of both cold sores and genital herpes in the community, avoiding exposure may be difficult. Some recommendations have been made. People with cold sores (particularly in active disease) should avoid:
  • Sharing personal items (i.e. toothbrushes, towels etc.);
  • Sharing drinking glasses/bottles or cutlery;
  • Close contact (such as kissing/hugging), particularly with newborns, young children, and people with weakened immune systems.
Genital herpes is generally passed through sexual contact. The lifetime number of sexual partners increases the risk of transmitting the infection. Consistent use of condoms has been suggested to minimize transmission. A pregnant mother with genital herpes may spread the virus to her newborn during labour. Post-partum infections may also occur when the baby is in contact with not just the mother, immediate family, and health workers, but also extended family and friends. Any individual who may be shedding the virus at the time (whether symptomatic or asymptomatic) may infect the baby. Immunesuppression is a common cause of reactivation and progression of the disease. Immune suppression may result from infections, haematological malignancies, or immune-suppressing drugs (such as chemotherapy in cancer patients, drugs in transplant patients, or high dose corticosteroids). Corticosteroids are commonly used in various rheumatological conditions and asthma.

Pathogenesis

Both HSV1 and HSV2 belong to the family of herpesviruses and specifically the alphaherpesviruses (see notes), thus share common characteristics. Their genome consists of double-stranded deoxyribonucleic acid (DNA) within an icosahedral nucleocapsid. Beyond this capsid, the virus is covered by a lipid membrane layer. This confers a susceptibility to environmental factors such as heat, and detergents or solvents. These viruses generally do not remain viable in the environment; direct inoculation is thus required for the infection to be transmitted. HSV infection can be divided between several phases:

Primary Infection

Acute infection
  • Transmission between hosts usually occurs via direct contact between muco-cutaneous membranes. Infection of skin may also occur with abrasions or excoriations compromising the integrity of the membrane.
  • The virus binds to proteins on the surface of cells which induces its entry into host cells. The host cellular mechanisms are then utilized to reproduce new viruses.
  • Release of these viruses usually results in localized spread.
  • Lesions that develop in this setting may be self-limiting
  • Primary infection is followed by production of virus which spreads systemically to sensory nerve endings (particularly of the trigeminal and sacral nerves).

Recurrence

Establishment & latency
  • The virus infects nerves via nerves endings, and travel along axons towards the nerve ganglia, where they lie dormant.

Reactivation

  • Lesions similar to the primary infection recur in the distribution of the trigeminal (mostly HSV1) and sacral (mostly HSV2) nerve ganglia.
  • Some triggers have been postulated such as emotional stress, sun exposure, and illness.
Systemic spread may also occur as seen in systemic infections and in immunocompromised individuals. This may occur during acute infection or during virus reactivation. Although active or symptomatic disease is generally associated with increased risk of transmitting the virus, some studies have shown that virus shedding (particularly HSV2) occurs even from asymptomatic individuals. This aids the virus in spreading as hosts may not be aware that they are able to pass the infection on to their partners.

Symptoms

Commonly, the herpes virus results in fluid-filled blisters on and around the site of infection. The blister will eventually ulcerate and heal over time. However, infection may occur at virtually any area of skin, with increasing risks when skin integrity is compromised.
Herpes simplex symptoms on the eye
Herpes simplex symptoms on the eye
HSV infection is characterized by lesions in the affected regions progressing over three stages: Developmental:
  • Prodromal (i.e. tenderness, burning, tingling, or discomfort)
  • Erythematous
  • Papular
Disease stage:
  • Vesicular
  • Ulcerative
  • Hard crust
Resolution:
  • Dry flaking
  • Residual swelling
These lesions usually resolve over one to two weeks. The lesions may be accompanied by other symptoms such as pain and tenderness, and a burning sensation. Systemic manifestations such as fevers, myalgias, and arthralgias may also occur. The blisters occur usually in either the oral or genital region. This may or may not be preceded by known contact with someone with HSV. Asymptomatic infections may also occur; in these cases, only serological studies can indicate the exposure.

Non-dermal symptoms

Other symptoms of HSV indicate herpes simplex keratitis (tenderness or redness around the eye, visual change or visual impairment including blindness), and herpes simplex encephalitis (neurological signs: confusion, cognitive impairment, loss of coordination, headache, seizures and vomiting). Untreated encephalitis may result in irreversible disability. Symptoms of meningitis may also be present (photophobia or light sensitivity, neck stiffness). Disseminated visceral infection may also occur in patients with severe immune compromise (e.g. Acquired Immune Deficiency Syndrome).

Treatments

Medical treatment of HSV infections is not always required as symptoms are usually self-limiting. Salt baths, analgesic medications, ice, and loose clothing may be helpful in providing symptomatic relief, particularly for genital herpes.

Guanosine treatment

Should treatment be warranted, guanosine analogues (such as Acyclovir and other related drugs) are commonly used. This treatment does not completely remove the virus, and recurrences frequently appear. 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 drugs for viral DNA-polymerase minimizes toxicity to non-viral host cells. The following doses have been suggested (Marques & Straus, 2008; CDC, 2006).
Drug Dose Frequency
Acyclovir 400mg Three times daily
Acyclovir 200mg Five times daily
Famiciclovir 250mg Three times daily
Valacylovir 1000mg Twice daily
Treatment via oral administration is recommended, lasting 7-10 days. Continued treatment beyond 10 days may be required. Topical treatment is discouraged. Intravenous administration may be required for more serious infections such as herpes encephalitis and disseminated infection. 10mg/kg tds for children and 10-15 mg/kg tds for adults over two to three weeks is recommended. Higher doses are suggested for neonatal infection: IV acyclovir, 20mg/kg every eight hours, for two to three weeks. It is suggested that the best treatment of Herpes Simplex Keratitis involves administration of acyclovir combined with interferon and debridement. Topical or oral acyclovir may be used. Corticosteroids may also be employed to reduce inflammation and reduce duration of illness. Unfortunately, visual impairment may result despite medical management. Corneal grafting is available, for which adjunct treatment with prophylactic acyclovir to prevent recurrence is recommended. The following treatments have been suggested for genital herpes (Therapeutic Guidelines Ltd., 2004):
Drug Dose Frequency
Valacyclovir 500mg orally 12-hourly for 5 days
Acyclovir 400mg orally 8-hourly for 5 days
Famiciclovir 125mg orally 12-hourly for 5 days

Other treatments:

Other treatment regimens may be required for severe cases or specific complications of the infection. Some drugs such as painkillers, as well as ice and salt baths are used to relieve symptoms, particularly for genital herpes. Neonatal infections also invariably require treatment. Despite the available options, medical treatment may not be necessary as the outbreaks are generally self-limiting.

Prevention

Preventing infection

Avoiding contact with individuals with HSV may be difficult due to the high prevalence rate in the community. Some practical suggestions have been made. People with cold sores (particularly in active disease) should avoid:
  • Sharing personal items (i.e. toothbrushes, towels etc.)
  • Sharing drinking glasses/bottles or cutlery
  • Close contact (such as kissing/hugging), particularly with newborns, young children, and people with a weakened immune system
Leone (2005) recommended daily suppressive therapy for asymptomatic individuals to reduce transmission rates. There are currently no effective vaccines against HSV available.

Preventing recurrences/complications

In general, patients are advised to avoid breaking the vesicles as this may result in scar formation and secondary infections. Regular medications (acyclovir) may be an option. Recurrences are still likely to occur but with reduced severity. Pregnant women with genital HSV infection are advised to deliver via Caesarean section to reduce the risk of neonatal HSV infection.

Prognosis

Lesions in herpes simplex are generally self-limiting. However, recurrences frequently occur. More significant complications may arise with herpes simplex keratitis, herpes simplex encephalitis, and neonatal herpes. Adequate treatment for herpes simplex keratitis has significantly reduced associated morbidity. Up to 90% of patients recover within one week of treatment. One series reported on 94 women with HSV seroconversion during pregnancy. Neonatal herpes is unlikely if seroconversion is complete prior to the time of labour. Of nine women who acquired the infection shortly before labour, four of their babies were infected, with one mortality. A 24% overall mortality rate for neonatal herpes has also been reported in a sample of 59 neonatal HSV infections. Herpes encephalitis carries a poor prognosis even with treatment. Of forty-two patients in one study, only 48% retained normal function, and a further 21% continued living independently but with reduced functioning. Another 12% more had severe neurological deficit.

References

  • Brown, Z. A., Selke, S., Zeh, J., Kopelman, J., Maslow, A., Ashley, R. L., et al. (1997). The acquisition of herpes simplex virus during pregnancy. New England Journal of Medicine, 337, 509-516. Abstract available from: http://content.nejm.org/cgi/content/abstract/337/8/509 [Accessed 9/12/2008].
  • Centre for Disease Control and Prevention. (2006). Morbidity and mortality weekly report: Sexually transmitted diseases treatment guidelines. Recommendations and Reports, 55, (RR-11).
  • Cunningham A. L., Taylor, R., Taylor, J., Marks, C., Shaw J., Minder, A. (2006). Prevalence of infection with herpes simplex virus types 1 and 2 in Australia: a nationwide population based survey. Sexually Transmitted Infections, 82, 164-168. Abstract available from: http://sti.bmj.com/cgi/content/abstract/82/2/164 [Accessed 9/12/2008].
  • Department of Human Services. (2007). Cold sores. State of Victoria [Online]. Available from: http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Cold_sores [Accessed 9/12/2008].
  • Foster, C. S., Barney, N. P. (1992). Systemic acyclovir and penetrating keratoplasty for herpessimplex keratitis. Documenta Ophthalmologica, 80(4), 363-369. Abstract available from: http://www.springerlink.com/content/k8800pm5w0w62n53/ [Accessed 9/12/2008].
  • International Herpes Management Forum. (2007). Genital herpes: The facts. Cambridge Medical Publications [Online]. [Accessed 9/12/2008, no longer online].
  • Jones, C., Cunningham, A., Isaacs, D. (2003). Report: Epidemiology of neonatal HSV infection in Australia, prospective national surveillance. [Accessed 9/12/2008, no longer online].
  • Leone, P. (2005). Reducine the risk of transmitting genital herpes: Advances in understanding and therapy. Current Medical Research and Opinion, 21(10), 1577-1582. Abstract available online [Accessed 9/12/2008]
  • Marques, A. R., Straus, S. E. (2008). Chapter 193: Herpes simplex. Fitzpatrick’s Dermatology in General Medicine (7th Edition). The McGraw-Hill Companies.
  • McGrath, N., Anderson, N. E., Croxson, M. C., Powell, K. F. (1997). Herpes simplex encephalitis treated with acyclovir: Diagnosis and long term outcome. Journal of Neurology, Neurosurgery, and Psychiatry, 63,321-326. Abstract available from: http://jnnp.bmj.com/cgi/content/abstract/63/3/321 [Accessed 9/12/2008].
  • Mertz, G. j. (1993). Epidemiology of genital herpes infections. Infectious Disease Clinics of North America, 7(4), 825-839. Abstract available online [Accessed 9/12/2008].
  • O’Brien, J. J., Campoli-Richards, D. M. (1989). Acyclovir: An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs, 37(3), 233-309. Abstract available from: http://www.ncbi.nlm.nih.gov/pubmed/2653790 [Accessed 9/12/2008].
  • Oliver, L., Walk, A., Kim, M., Zeh, J., Selke, S., Ashley, R., et al. (1995). Seroprevalence of herpes simplex virus infections in a family medicine clinic. Archives of Family Medicine, 4(3), 228-232. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/7881604 [Accessed 9/12/2008].
  • Pritz, T. (2007). Herpes simplex encephalitis. emedicine [Online]. Available from: http://www.emedicine.com/emerg/TOPIC247.HTM [Accessed on 9/12/2008].
  • Siegel, D., Golden, E., Washington, A. E., Morse, S.A., Fullilove, M. T., Catania, J. A., et al. (1992). Prevalence and correlates of herpes simplex infections: the population-based AIDS in multiethnic neighborhoods study. Journal of the American Medical Association, 268(13), 1702-1708. Abstract available from: http://jama.ama-assn.org/cgi/content/abstract/268/13/1702 [Accessed 9/12/2008].
  • 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). Genital skin diseases. Therapeutic Guidelines: Dermatology 2nd Edition. 201-220. Therapeutic Guidelines Limited.
  • Wang, J. C. (2007). Keratitis, herpes simplex. emedicine [Online]. Available from: http://www.emedicine.com/oph/topic100.htm [Accessed on 9/12/2008].
  • Wilhelmus, K. R. (2007). Antiviral, interferon, and debridement treatments for herpes simplex eye disease. Cochrane Database of Systematic Reviews, 3, Art. No.: CD002898. DOI: 10.1002/14651858.CD002898.pub3. Abstract available from: http://www.cochrane.org/reviews/en/ab002898.html [Accessed on 9/12/2008].
  • Wilhelmus, K. R., Gee, L., Hauck, W. W., Kurinji, N., Dawson, C. R., Jones, D. B., et al. (1994). Herpetic eye disease study: A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Opthalmology, 101(12), 1895-1896. Abstract available from: http://www.ncbi.nlm.nih.gov/pubmed/7997324?dopt=Abstract [Accessed 9/12/2008].
  • Young, S. K., Rowe, N. H., Buchanan, R. A. (1976). A clinical study for the control of facial mucocutaneous herpes virus infections. I. Characterization of natural history in a professional school population. Oral Surgery, Oral Medicine, and Oral Pathology, 41(4), 498-507. Abstract available from: http://www.ncbi.nlm.nih.gov/pubmed/1063349 [Accessed 9/12/2008].

Online resources

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Snapshot
Other common terms: VZV, chickenpox (varicella), shingles (herpes zoster)
ICD-10 classification: B01, B02
Prevalence: Very common with up to 1,500:100,000 reported.
Causes: Airborne transmission
Symptoms: Incubation period (2 weeks): fever, general malaise, abdominal pain, headache. Followed by skin lesions; a rash which eventually crust and heal.
Treatments/cures: No known cure. Treatment is generally avoided except in extreme cases. Relief of rash is mainstay of treatment.
Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
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. 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.

Incidence

VZV infection was quite common prior to the introduction of the vaccine in 1995. Incidence rates of 1,500-1,600 per 100,000 have been reported in the USA. Since the introduction of the vaccine, reported incidence rates have markedly decreased. 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. 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.

Causes

Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
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. 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. VZV belongs to the family of herpesviruses and specifically the alphaherpesviruses. 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. 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. 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. 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. Following this, the virus forms a latent infection within nerve ganglia. 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. The host’s cellular mechanisms are then utilized to reproduce new viruses. Both humoral and cellular immunity is important in containing the infection. In immunocompromised patients, severe complications of VZV are more likely to occur

Symptoms

Skin lesion (shingles) from VZV infection
Skin lesion (shingles) from VZV infection
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 hard crusts that 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. 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. 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. 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. 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. Complications of herpes zoster include postherpetic neuralgia, and neurological involvement. Approximately 9% of patient with herpes zoster develop postherpetic neuralgia, which is characterised 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.

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. Treatment of immunocompromised adults with varicella with acyclovir does not improve skin healing rates, but can significantly reduced visceral complications. Acyclovir 10mg/kg for 7-10 days has been recommended. Administration via intravenous route over eight hours is preferred. 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. Treatment is required for all patients with herpes zoster. The following regimens are recommended by Therapeutic Guidelines Ltd. (2004):
Drug Dose (oral) Frequency (Duration of 7 days)
Acyclovir 20mg/kg for children Five times daily
Acyclovir 800mg for adults Five times daily
Famiciclovir 250mg 8 hourly
Valacylovir 1000mg 8 hourly

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:

Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
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.

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]. [Accessed on 9/12/2008, no longer online].
  • 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. Link no longer active.].
  • 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. [Accessed on 10/12/2008]
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  • Zimmerman, R K (1996). ‘Varicella vaccine: Rationale and indications for use’. American Family Physician [Online]. [Accessed on 10/12/2008, no longer online].

Online resources

Better Health Channel, Victoria:

Online associations

Snapshot

Other common terms:Cold sores, herpes, genital herpes, HSV
ICD-10 classification: A60, >B00, P35.2
Prevalence:  HSV1 56-76% of general population, HSV2 23-33% of general population
Causes: Direct contact infection; genital herpes (HSV2) is a sexually transmitted infection (STI)
Symptoms:Fluid-filled blisters on and around the site of infection.
Treatments/cures:  Cannot be cured. Treatment with guanosine analogues is common.

Herpes simplex virus (HSV) infection (called cold sores and genital herpes depending on the site of infection) is a common infection which results from contact with persons or hosts who have the infection.

Whilst HSV infections generally have good prognosis, important complications may occur, particularly with immunocompromised patients or neonates.

Incidence

Herpes is quite common in the community. Unfortunately, as cold sores and genital herpes are not a notifiable diseases, epidemiological data is limited.

The virus can be acquired from a very young age. The rate of HSV infection rises with age, and eventually, most people would have been exposed. Figures between 56-76% of the population (see below) have been reported to have been infected by HSV1. The prevalence of HSV2 is much lower (23-33%), and is mostly associated with increasing sexual activity. Thus the incidence increases with older age, particularly with a higher number of lifetime sexual partners.

Other rarer complications may result from HSV infection. These usually occur in immunesuppressed patients. Possible complications include herpes simplex keratitis, and herpex simplex encephalitis. Permanent damage my result including, visual impairment, and cognitive or neurological impairment.

Neonatal infections are rare (reported as 3.9 in 100,000 live births). However, the mortality rate is relatively high (24%), and long-term sequelae may occur.

Herpes Simplex Virus magnified

Herpes is quite common in the community. Unfortunately, as cold sores and genital herpes are not a notifiable diseases, epidemiological data is limited.

The virus can be acquired from a very young age. The rate of HSV infection rises with age, and eventually, most people would have been exposed. Figures between 56-76% of the population (see below) have been reported to have been infected by HSV1. The prevalence of HSV2 is much lower (23-33%), and is mostly associated with increasing sexual activity. Thus the incidence increases with older age, particularly with a higher number of lifetime sexual partners.

Other rarer complications may result from HSV infection. These usually occur in immunesuppressed patients. Possible complications include herpes simplex keratitis, and herpex simplex encephalitis. Permanent damage my result including, visual impairment, and cognitive or neurological impairment.

Neonatal infections are rare (reported as 3.9 in 100,000 live births). However, the mortality rate is relatively high (24%), and long-term sequelae may occur.

 

Known incidence studies on HSV infection

An Australian survey found 76% of 4000 participants to be seropositive for HSV1, and 12% of participants to be seropositive for HSV2. Similar results have been published in American studies. Siegel et al. (1992) reported on a community-based survey with sample size of 1212 individuals. Of these participants, 62% were seropositive for HSV1 and 33% were positive for HSV2. A higher prevalence rate was associated with increased age, and less education (for both HSV1 and HSV2). In addition, a higher rate of HSV2 infection correlated with being female, and the number of lifetime sexual partners.

A similar study at a family medicine clinic found 56% of patients seropositive for HSV1, and 23% seropositive for HSV2. In summary, the majority of the population would have been exposed to HSV.

Causes

While genital herpes is considered to be a sexually transmitted infection, any form of contact is a possible route of infection. For example direct contact, and even through shared items. Unfortunately, due to the high prevalence of both cold sores and genital herpes in the community, avoiding exposure may be difficult. Some recommendations have been made. People with cold sores (particularly in active disease) should avoid:

  • Sharing personal items (i.e. toothbrushes, towels etc.);
  • Sharing drinking glasses/bottles or cutlery;
  • Close contact (such as kissing/hugging), particularly with newborns, young children, and people with weakened immune systems.

Genital herpes is generally passed through sexual contact. The lifetime number of sexual partners increases the risk of transmitting the infection. Consistent use of condoms has been suggested to minimize transmission.

A pregnant mother with genital herpes may spread the virus to her newborn during labour. Post-partum infections may also occur when the baby is in contact with not just the mother, immediate family, and health workers, but also extended family and friends. Any individual who may be shedding the virus at the time (whether symptomatic or asymptomatic) may infect the baby.

Immunesuppression is a common cause of reactivation and progression of the disease. Immune suppression may result from infections, haematological malignancies, or immune-suppressing drugs (such as chemotherapy in cancer patients, drugs in transplant patients, or high dose corticosteroids). Corticosteroids are commonly used in various rheumatological conditions and asthma.

Pathogenesis

Both HSV1 and HSV2 belong to the family of herpesviruses and specifically the alphaherpesviruses (see notes), thus share common characteristics. Their genome consists of double-stranded deoxyribonucleic acid (DNA) within an icosahedral nucleocapsid. Beyond this capsid, the virus is covered by a lipid membrane layer. This confers a susceptibility to environmental factors such as heat, and detergents or solvents. These viruses generally do not remain viable in the environment; direct inoculation is thus required for the infection to be transmitted.

HSV infection can be divided between several phases:

 

Primary Infection

Acute infection
  • Transmission between hosts usually occurs via direct contact between muco-cutaneous membranes. Infection of skin may also occur with abrasions or excoriations compromising the integrity of the membrane.
  • The virus binds to proteins on the surface of cells which induces its entry into host cells. The host cellular mechanisms are then utilized to reproduce new viruses.
  • Release of these viruses usually results in localized spread.
  • Lesions that develop in this setting may be self-limiting
  • Primary infection is followed by production of virus which spreads systemically to sensory nerve endings (particularly of the trigeminal and sacral nerves).

 

Recurrence

Establishment & latency
  • The virus infects nerves via nerves endings, and travel along axons towards the nerve ganglia, where they lie dormant.
  •  

Reactivation

  • Lesions similar to the primary infection recur in the distribution of the trigeminal (mostly HSV1) and sacral (mostly HSV2) nerve ganglia.
  • Some triggers have been postulated such as emotional stress, sun exposure, and illness.

Systemic spread may also occur as seen in systemic infections and in immunocompromised individuals. This may occur during acute infection or during virus reactivation.

Although active or symptomatic disease is generally associated with increased risk of transmitting the virus, some studies have shown that virus shedding (particularly HSV2) occurs even from asymptomatic individuals. This aids the virus in spreading as hosts may not be aware that they are able to pass the infection on to their partners.

Symptoms

Commonly, the herpes virus results in fluid-filled blisters on and around the site of infection. The blister will eventually ulcerate and heal over time. However, infection may occur at virtually any area of skin, with increasing risks when skin integrity is compromised.

HSV infection is characterized by lesions in the affected regions progressing over three stages: 

Developmental:

  • Prodromal (i.e. tenderness, burning, tingling, or discomfort)
  • Erythematous
  • Papular

Disease stage:

  • Vesicular
  • Ulcerative
  • Hard crust

Resolution:

  • Dry flaking
  • Residual swelling

Herpes simplex symptoms on the eye

These lesions usually resolve over one to two weeks. The lesions may be accompanied by other symptoms such as pain and tenderness, and a burning sensation. Systemic manifestations such as fevers, myalgias, and arthralgias may also occur.

The blisters occur usually in either the oral or genital region. This may or may not be preceded by known contact with someone with HSV. Asymptomatic infections may also occur; in these cases, only serological studies can indicate the exposure.

 

Non-dermal symptoms

Other symptoms of HSV indicate herpes simplex keratitis (tenderness or redness around the eye, visual change or visual impairment including blindness), and herpes simplex encephalitis (neurological signs: confusion, cognitive impairment, loss of coordination, headache, seizures and vomiting). Untreated encephalitis may result in irreversible disability. Symptoms of meningitis may also be present (photophobia or light sensitivity, neck stiffness). Disseminated visceral infection may also occur in patients with severe immune compromise (e.g. Acquired Immune Deficiency Syndrome).

Treatments

Medical treatment of HSV infections is not always required as symptoms are usually self-limiting. Salt baths, analgesic medications, ice, and loose clothing may be helpful in providing symptomatic relief, particularly for genital herpes.

 

Guanosine treatment

Should treatment be warranted, guanosine analogues (such as Acyclovir and other related drugs) are commonly used. This treatment does not completely remove the virus, and recurrences frequently appear.

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 drugs for viral DNA-polymerase minimizes toxicity to non-viral host cells.

The following doses have been suggested (Marques & Straus, 2008; CDC, 2006).

Drug
Dose (oral)
Frequency
Acyclovir
400mg
Three times daily
Acyclovir
200mg
Five times daily
Famiciclovir
250mg
Three times daily
Valacylovir
1000mg
Twice Daily

Treatment via oral administration is recommended, lasting 7-10 days. Continued treatment beyond 10 days may be required. Topical treatment is discouraged.

Intravenous administration may be required for more serious infections such as herpes encephalitis and disseminated infection. 10mg/kg tds for children and 10-15 mg/kg tds for adults over two to three weeks is recommended. Higher doses are suggested for neonatal infection: IV acyclovir, 20mg/kg every eight hours, for two to three weeks.

It is suggested that the best treatment of Herpes Simplex Keratitis involves administration of acyclovir combined with interferon and debridement. Topical or oral acyclovir may be used. Corticosteroids may also be employed to reduce inflammation and reduce duration of illness. Unfortunately, visual impairment may result despite medical management. Corneal grafting is available, for which adjunct treatment with prophylactic acyclovir to prevent recurrence is recommended.

The following treatments have been suggested for genital herpes (Therapeutic Guidelines Ltd., 2004):

Drug
Dose (oral)
Frequency
Valacyclovir
500mg orally
12-hourly for 5 days
Acyclovir
400mg orally
8-hourly for 5 days
Famiciclovir
125mg orally
12-hourly for 5 days

Other treatments:

Other treatment regimens may be required for severe cases or specific complications of the infection. Some drugs such as painkillers, as well as ice and salt baths are used to relieve symptoms, particularly for genital herpes.
Neonatal infections also invariably require treatment.
Despite the available options, medical treatment may not be necessary as the outbreaks are generally self-limiting.

Prevention

Preventing infection

Avoiding contact with individuals with HSV may be difficult due to the high prevalence rate in the community. Some practical suggestions have been made. People with cold sores (particularly in active disease) should avoid:

  • Sharing personal items (i.e. toothbrushes, towels etc.)
  • Sharing drinking glasses/bottles or cutlery
  • Close contact (such as kissing/hugging), particularly with newborns, young children, and people with a weakened immune system

Leone (2005) recommended daily suppressive therapy for asymptomatic individuals to reduce transmission rates. There are currently no effective vaccines against HSV available.

 

Preventing recurrences/complications

In general, patients are advised to avoid breaking the vesicles as this may result in scar formation and secondary infections.
Regular medications (acyclovir) may be an option. Recurrences are still likely to occur but with reduced severity.
Pregnant women with genital HSV infection are advised to deliver via Caesarean section to reduce the risk of neonatal HSV infection.

Prognosis

Lesions in herpes simplex are generally self-limiting. However, recurrences frequently occur.

More significant complications may arise with herpes simplex keratitis, herpes simplex encephalitis, and neonatal herpes.

Adequate treatment for herpes simplex keratitis has significantly reduced associated morbidity. Up to 90% of patients recover within one week of treatment.

One series reported on 94 women with HSV seroconversion during pregnancy. Neonatal herpes is unlikely if seroconversion is complete prior to the time of labour. Of nine women who acquired the infection shortly before labour, four of their babies were infected, with one mortality. A 24% overall mortality rate for neonatal herpes has also been reported in a sample of 59 neonatal HSV infections.

Herpes encephalitis carries a poor prognosis even with treatment. Of forty-two patients in one study, only 48% retained normal function, and a further 21% continued living independently but with reduced functioning. Another 12% more had severe neurological deficit.

References
  • Brown, Z. A., Selke, S., Zeh, J., Kopelman, J., Maslow, A., Ashley, R. L., et al. (1997). The acquisition of herpes simplex virus during pregnancy. New England Journal of Medicine, 337, 509-516. Abstract available from: http://content.nejm.org/cgi/content/abstract/337/8/509 [Accessed 9/12/2008].
  • Centre for Disease Control and Prevention. (2006). Morbidity and mortality weekly report: Sexually transmitted diseases treatment guidelines. Recommendations and Reports, 55, (RR-11).
  • Cunningham A. L., Taylor, R., Taylor, J., Marks, C., Shaw J., Minder, A. (2006). Prevalence of infection with herpes simplex virus types 1 and 2 in Australia: a nationwide population based survey. Sexually Transmitted Infections, 82, 164-168. Abstract available from: http://sti.bmj.com/cgi/content/abstract/82/2/164 [Accessed 9/12/2008].
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  • Foster, C. S., Barney, N. P. (1992). Systemic acyclovir and penetrating keratoplasty for herpessimplex keratitis. Documenta Ophthalmologica, 80(4), 363-369. Abstract available from: http://www.springerlink.com/content/k8800pm5w0w62n53/ [Accessed 9/12/2008].
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