Science of Skin

Herpes Simplex Virus (HSV)

Snapshot
Other common terms: Cold sores, herpes, genital herpes, HSV
ICD-10 classification: A60, asrc="plugins/editors/jce/tiny_mce/themes/advanced/langs/en.js?version=156" target="_blank" href="http:/>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]. Available from: http://www.ihmf.org/general/resources03.asp [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. Previously available from: http://www.chs.usyd.edu.au/conf04/submit/minipost/fu-jones.pdf [Accessed 9/12/2008]..
  • 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

Online associations

Quick Links