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Herpes simplex: diagnosis and treatment

The Herpes simplex virus causes cold sores on the face (H labialis), whitlows on the fingers and hands and genital herpes (H genitalis). It may also infect other areas of the skin. Prevalence in adults in the UK is about 60%, worldwide it nears 90%. Since most infected people are asymptomatic, rates are detected through blood tests for H simplex antibodies.
There are two genotypes, type 1 being much more common than type 2. In the UK, 25% of all 12-year-olds have type 1; by the age 30 this has risen to 50%.(1) After childhood, type 1 is caught equally on the face or genitals; up to 60% of new genital infection is type 1.(2) Prior infection with type 1 lessens the clinical manifestations of first infection by type 2.(3) Symptoms and treatment are identical for both types, so both are referred to as herpes simplex unless specifically differentiated.
There are nine viruses in the family of "human herpes viruses", which all set up latency and can reactivate periodically. Varicella zoster, the cause of herpes varicella and herpes zoster (chickenpox and shingles), is very similar to H simplex - it causes skin infections and remains dormant in the sensory ganglia. The other viruses in the herpes family may cause systemic infection (eg, the Epstein-Barr virus causes glandular fever).

Latency and recurrences
H simplex remains dormant in the sensory dorsal root ganglion serving the affected dermatome - the trigeminal ganglion for facial infection and the sacral ganglia for genital infection. It may reactivate periodically. Frequency of recurrences varies widely: type 1 recurs more frequently on the face, and type 2 recurs more frequently on the genitals. Genetic inheritance and general health determine frequency of recurrences.
A recurrence appears only in the infected dermatome. Facial infection can recur from the jaw to the crown of the head. Genital infection can recur perianally, on lower buttocks and back of thighs - 49% of female and 19% of male members of the Herpes Viruses Association (HVA) report perianal recurrences.(4) After the primary infection is resolved, immunocompetent persons do not reinfect themselves on other sites.(5)

Eye infection
Virus latent in the trigeminal ganglion may reactivate in the ophthalmic division of the trigeminal nerve causing pain in, usually, one eye. Diagnosis is by fluoroscein stain.

Encephalitis
Rarely, in two cases per million, virus latent in the trigeminal ganglion may affect the brain. Recent research suggests that encephalitis only affects individuals with an immunodeficiency on a single gene.(6)

Transmission and incubation
Transmission is by direct skin-to-skin contact with the affected part when the virus is active, mainly through mucous membrane. It can affect other areas of skin entering through often undetected fissures in ordinary skin. The incubation period is usually two to 14 days; however, subjects may carry the virus asymptomatically for years before becoming symptomatic.
Tiny amounts of virus and viral particles have only been occasionally detected in genital swabs from half the subjects of a trial even when no symptoms were seen. This asymptomatic shedding occurred mainly just before and just after outbreaks. Rates of asymptomatic shedding are highest in the first six months of infection and decline rapidly, becoming very rare two years after infection. Asymptomatic shedding is as common in the saliva and tears of people with cold sores.(7)
Transmission is not through towels, cutlery, swimming pools, and so on. The virus dies immediately if not kept moist and at body temperature.
Patients are rarely concerned about transmission of facial cold sores, but should be advised not to kiss young infants and people lacking an adequate immune response when a sore is present. Individuals with atopic dermatitis are at risk of eczema herpeticum and should avoid skin-to-skin contact with people with active herpes lesions (especially orofacial lesions).
The importance of genital infection is exaggerated in many websites, articles and reference books. Herpes simplex is seldom medically significant and is usually self-limiting. However, for some patients counselling may be necessary (see "Psychological effects" below.)

Symptoms
Three-quarters of infections will be asymptomatic, or symptoms will be mild and unrecognised. The primary illness lasts about two to three weeks and is self-limiting. Typical signs and symptoms may include:

  • Fever and aching body.
  • Neuralgia, described variously as scalded skin, deep aches, tingling or shooting nerve pains in the affected dermatome.
  • Blisters (on ordinary skin).
  • Sores or ulcers (on mucous membranes).
  • Tender, swollen lymph glands near site of infection (usually bilateral in primary infection).
  • Painful or difficult urination (genital infection).
  • Vaginal or urethral discharge (genital infection).

Complications

  • Gingivostomatitis (facial infection, commonly seen in paediatrics and probably primary infection), with resultant difficulty in eating/drinking.
  • Autonomic neuropathy, resulting in urinary
  • retention (genital infection).
  • Eczema herpeticum: individuals with atopic
  • dermatitis may acquire herpes simplex over a wider area with more severe symptoms
  • Central nervous system infections, caused equally by type 1 or 2, either with primary infection or long after. Such infections are diagnosed by PCR (polymerase chain reaction) of cerebrospinal fluid:
    i. Aseptic meningitis is quite common but does not cause any long-term problems.(8)
    ii. Herpes encephalitis is rare (200 cases a year).  Symptoms are lowered (or altered) consciousness, also confusion, drowsiness, seizures and coma.(9)

Recurrent episodes are rarely preceded by systemic symptoms. However, neuropathic sensations in the affected dermatome may presage an outbreak: these prodromes may be itching, tingling, burning, aching or stabbing. Lymphadenitis is unilateral. There are fewer blisters. Recurrences may be very mild and difficult to recognise: redness, itching area, "a sore place", small cut(s).  Time to healing may be measured in days instead of weeks. With time, recurrences usually diminish both in frequency and duration.

Diagnosis
Facial cold sores are self-diagnosed or diagnosed clinically by GPs. Genital infection may be self-diagnosed or diagnosed clinically.5 Genitourinary (GUM) clinics use viral culture tests that directly demonstrate herpes simplex virus in swabs taken from the base of the genital lesion.
Patients with a new genital infection should be referred to a GUM clinic for a full STI screening. This must be on the same day, as diagnosis of herpes simplex requires actively forming sores.(10)

Treatments
First episode
If the primary infection (labial or genital) is severe, a course of antiviral drugs is indicated. Otherwise use antipyretics, analgesics and topical anaesthetics (lidocaine, EMLA) as appropriate. Rinsing with a saline solution may be soothing (one teaspoon to one pint of warm water).(11)

Use of antiviral drugs

  • Start oral antivirals as soon as possible.
  • Aciclovir, valaciclovir and famciclovir all reduce the severity and duration of episodes but do not alter the prognosis of the disease.
  • All antiviral agents have been found to be similarly effective in reducing the duration of symptoms and viral shedding compared with placebo. One RCT found no difference between valaciclovir taken for three versus five days.(12)
  • If new lesions are still appearing, a further course of five days may be given.
  • Topical antiviral therapy, on its own or with antiviral tablets, offers little benefit.

Management of complications

  • Labialis: use anaesthetic gel for teething (babies/children) or mouth ulcers (adults) and offer ice cubes to suck on. Hospitalisation may be required for gingivostomatitis if the patient cannot eat or drink, meningism and severe constitutional symptoms.
  • Intravenous therapy is only indicated when the patient cannot swallow or tolerate oral medication because of vomiting.
  • Genitalis: hospitalisation may be required for urinary retention, meningism and severe constitutional symptoms.
  • Encephalitis: intravenous aciclovir is indicated for adults and children older than three months.

Recurrences
Recurrences are self-limiting and generally cause minor symptoms. Patients may choose to self-manage. Treatment needs may vary over time according to recurrence frequency, symptom severity and relationship status. For severe or frequent recurrences, antiviral treatment may be given prophylactically or episodically.

Treating recurrences
Suppressive therapy for a period of six months (minimum useful treatment) is usually reserved for patients who have had at least six recurrences per annum. There is now over 13 years of safety and resistance data on patients on long-term therapy with aciclovir.
An alternative is episodic treatment, which is shown to reduce the duration (by median of one to two days). The regimen is the same as for the first episode. Recently, however, high doses for a shorter period have been shown to be as effective: a quadruple dose for one day.(13) Episodic treatment should be self-initiated when prodromes are noticed.
Self-help is also often effective: analgesics and topical anaesthetics (lidocaine). The Herpes Virus Assocation can suggest some other available treatments, including herbal treatments.(14,15)
Aciclovir cream has little effect on H labialis or
H genitalis.(16) If treatment is necessary, antiviral tablets should be prescribed.

Complications of H labialis

  • Eye infection: treatment with antiviral ophthalmic cream as well as antiviral pills is indicated. Eye infection may cause impaired vision or even, rarely, cause blindness. A patient who has suffered two ophthalmic outbreaks should be given antiviral therapy and instructed to initiate treatment as soon as prodromes occur.
  • Encephalitis: intravenous antiviral treatment is vital. If untreated, the prognosis is poor.

Aciclovir, famciclovir and valaciclovir suppress symptomatic and asymptomatic viral shedding. These drugs have been shown in clinical trials to reduce transmission from an average of 3.6% to an average of 1.9%.

Pregnancy
Most women with H simplex are unaware of their condition and give birth normally without problem. The British Paediatric Surveillance Unit found that an average of 13 babies a year develop H simplex type 1 or 2 in the neonatal period, with a fatality rate of 4.5.(17)
Only women who acquire H simplex in the third trimester should be offered a caesarean section for the prevention of neonatal herpes.(18) Antiviral therapy can be given to speed healing of lesions and may be continued to ensure no recurrence before delivery.
If the virus was caught before conception, or during the first or second trimester, the mother will have developed specific antibodies. These antibodies are transmitted to the baby (transplacental/passive immunity, maternal antibody). The baby has the same antibodies as the mother, and these give protection during a normal delivery even if the virus is present in the birth canal. Culturing swabs taken during the final weeks of pregnancy is pointless, since this does not predict viral shedding at term. Aciclovir suppressive treatment from 36 weeks gestation may be considered if the mother is anxious.

Psychological effects
Many patients find a genital herpes diagnosis distressing. This is largely a consequence of the original aciclovir marketing campaign. Sexually transmitted conditions carry a stigma, "exacerbated in this country by an immature attitude to sex, characterised by prurience and prudery," says Mr Peter Greenhouse, BASHH's media spokesperson.(19) The "herpes hype" and associated stigma mean that most people remain secretive about it.
Women, in particular, should be reassured about two common myths: H simplex is not a causal factor for cervical cancer, and women who catch H simplex before conception need not assume they will need a caesarean section.

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References

  1. Vyse AJ, Gay NJ, Gopal R, et al. The burden of infection with HSV-1 and HSV-2 in England and Wales; implications for the changing epidemiology of genital herpes. Sex Transm Infect 2000;76:183-7.
  2. Patel R, Cowan F, Barton S.
  3. Advising patients with genital herpes. BMJ 1997;314:85-6.
  4. Langenberg AG, Corey L, Ashley RL, et al. A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group. N Engl J Med 1999;341:1432-8.
  5. Wolfe M, Nicholson M. Unpublished data from questionnaire responses from 234 members of HVA, 1997. Mindel A, Carney O. Herpes: what it is and how to cope. London: Optima; 1991.
  6. Casrouge A, Zhang SY, Eidenschenk C, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 2006;314:308-12.
  7. Corey L. Clinical tools for preventing sexual transmission of genital herpes. Medscape Infectious Diseases 2004. Available from:
    http://www.medscape.com/viewarticle/472427
  8. International Herpes Management Forum guidelines. Available from:
    http://www.ihmf.org/library/powerpoint/pp_k8_11.ppt#5
  9. The Encephalitis Society. Available from:
    http://www.encephalitis.info/TheIllness/TypesEncephalitis/HSE.html
  10. Prodigy guidelines. Available from: http://www.prodigy.nhs.uk
  11. British Association of Sexual Health and HIV guidelines. Available from: http://www.bashh.org/guidelines/2002/hsv_0601.pdf
  12. Jungmann EM. Genital herpes. Clin Evid Concise 2004:11:390-3.
  13. Sacks SL, Aoki FY, Diaz-Mitoma F, et al, for the Canadian Famciclovir Study. Patient initiated, twice daily oral famciclovir for early recurrent genital herpes: a randomized, double-blind multicenter trial. JAMA 1996;276:44-9.
  14. Williams M. Immuno-protection against herpes simplex type II infection by eleutherococcus root extract. Int J Alt Complement Ther 1995;13(7):9-12.
  15. Nicholson M, Scott N. Report on our study shows olive leaf the winner. Sphere 2000;14(4):1-2.
  16. Update on drugs for herpes zoster and genital herpes. Drug Ther Bull 1998;36(10):77-9.
  17. Tookey P, Peckham CS. Neonatal herpes simplex virus infection in the British Isles. Paediatr Perinat Epidemiol 1996;19:432-42.
  18. NICE CG13. Caesarean section. Summary of effects and procedural aspects. Available from:http://www.nice.org.uk/download.aspx?o=cg013algorithm
  19. Greenhouse P. Destigmatising sexual health clinics. Br J Sex Med 1996;23(5):13-5.