Herpes Simplex Virus

last authored: Jan 2012, Lindsey Sutherland
last reviewed: Jan 2012, Tahmeena Ali

 

 

Introduction

Herpes Simplex Virus (HSV) is a double-stranded DNA virus within the Herpesviridae family.

 

There are two types of HSV: HSV-1 which is responsible for the majority of oral lesions (herpes labialis); and HSV-2, one of the most common sexually transmitted infections that results in genital lesions (herpes genitalis). However, HSV-1 and HSV-2 can be responsible for either oral or genital herpes.

 

HSV oral and genital lesions are generally localized eruptions of the skin and mucous membranes: clustered, painful vesicles on an erythematous base; however, HSV-1 genital infections can present as painless lesions. The vesicles rapidly break open to an ulcerative form of lesion that crust and heal over. With the primary infection, 4-7 days after exposure, additional symptoms and signs may include: fever, myalgias, headache, lymphadenopathy, and cervicitis. This is then followed by the vesicular outbreak; however up to 80% of HSV infections are asymptomatic (Salvaggio et al. 2010).

return to top

 

 

 

The Case of Natalie S.

Natalie is a 21 year-old female who presents to clinic with a one week history of non-painful, non-itchy blisters and ulcers around her vagina. On further questioning, she reports she has been feeling well and denies fever, aches and pains, or headache in the last couple of weeks. She noticed the blisters while showering and has been trying some polysporin on them, which she thinks may have helped a bit, as now most of the blisters have popped and just ulcers remain.

 

On history, she is otherwise healthy. She works at the local grocery store where she met her new boyfriend, a truck driver for the grocery store chain. They have been together a month and had their first sexual experience a couple weeks ago with oral and vaginal sex. She says that she remembers her boyfriend had a cold sore around his mouth at the time of the oral sex.

 

On exam, her vitals are normal, abdominal exam is unremarkable. There is a 2-3cm line of ulcers with an erythematous background on the vaginal vestibule bilaterally, with 1-2 non-erupted vesicles at the top of the line on the right side. There is no significant vaginal discharge, although her cervix is erythematous and friable. No cervical motion tenderness is elicited and examination of the adnexa is normal. No inguinal lymphadenopathy.

• What is on your list of differential diagnoses?
• How would you diagnose Natalie’s lesions?
• What treatment and management plan would you offer her?
• Is there any specific education you would want to provide her with?

 return to top

 

 

 

Epidemiology

Worldwide, the prevalence of HSV-1 ranges from 45% to >90%, with a strong predominance amongst lower socioeconomic status (SES) groups, underdeveloped countries, and HIV positive individuals (Smith et al. 2002). The prevalence of HSV-1 in developed nations is declining. However, the worldwide HSV-2 seroprevalence has been increasing over the past 20 years (Salvaggio et al. 2010).

 

A few specific populations are at greatest risk for HSV-1 infections:

• Contact sport athletes such as wrestlers
• Nurses and other medical professionals were found to have a lower rate of seroprevalence and  therefore are at increased risk for primary HSV infection;  which stresses the importance of universal precautions;
• Immunocompromised (eg/chemotherapy patients, previous organ transplantation, HIV +) individuals have increased morbidity and mortality from HSV. There is an increased risk for seroconversion and more aggressive outbreaks with comorbid HIV/HSV infections. 

 return to top

 

 

 

Transmission and Infection

HSV is highly contagious with a 75% transmission rate. The virus stays latent in the nerve root and therefore those infected are carriers for life, with or without recurrent episodes of symptoms (Dynamed Herpes Genitalis, 2011). Transmission rates are reduced with the use of long-term suppressive antiviral treatment, such as daily valacyclovir therapy: this can be especially useful in immunocompromised patients (Corey et al. 2004). Transmission occurs by direct contact with skin or mucosal secretions. More women are affected by genital herpes than men, due to the mechanism of sexual intercourse making women at higher risk of contracting the virus from men. Due to viral shedding, transmission can occur even when the infected host is asymptomatic. However, the rate of transmission is highest in the presence of active lesions; therefore sexual contact during this time should be avoided.

 

Neonatal herpes is primarily acquired by vertical transmission during passage through the genital tract with delivery, mainly in the presence of active genital herpes lesions. This accounts for 85-90% of cases. Women with a primary HSV infection during their third trimester that remains active during delivery have a 33% chance of transmitting the infection to their infant, compared to a risk of only 3% in women with a secondary reactivation of HSV during this time. Active disease is an absolute contraindication for vaginal delivery and requires Caesarean delivery. Intrauterine infection occurs about 5% of the time, with the highest rate of transmission early in pregnancy leading to abortion, stillbirth, or congenital abnormalities at birth. (Rudnick et al. 2002).

Postnatal infections (~5%) can occur from contact with infected parents or healthcare professionals. Prevention of maternal primary HSV infection during pregnancy and prevention of vertical transmission during vaginal delivery is imperative (Dynamed Neonatal Herpes, 2011).

return to top

 

 

  

Clinical Manifestations

Primary herpes labialis

Often, there is a prodrome of a fever, followed by the eruption of mouth lesions commonly associated with submandibular and cervical lymphadenopathy. In a primary infection, the mouth lesions are known as herpetic gingivostomatitis and they classically present as painful vesicles found over a red, swollen base. These are usually found on the lips, gingival, oral palate, and tongue. The vesicles ulcerate and can be extremely painful, often causing avoidance of eating or drinking by those affected. Within 10-14 days the lesions are healed.

 

Recurrent herpes labialis: The recurrent oral herpes presents much differently with a common prodrome of tingling, pain, paresthesias, itching, and burning. It is at this time when taking episodic antiviral treatment can be most effective. The lesions that develop are vesicular clusters on an erythematous base located along the vermillion border and on the lip. These lesions also ulcerate and will crust over to heal within 7-8 days.

 

Primary herpes genitalis

If symptomatic, there is often a prodrome of fever, headache, fatigue and muscle pains. This is followed by local pain, pruritus, dysuria, vaginal and urethral discharge, and tender lymphadenopathy.

 

In HSV-1, the outbreak may be painless and without the prodrome symptoms.

 

In men, the vesicles can appear on the glans penis, prepuce, shaft, and may be found on the scrotum, thighs, and buttocks. The perianal area and rectum may be involved in persons engaging in anal intercourse. Dysuria can be severe and cause urinary retention, often associated with urethritis.

 

In women, the vesicles can appear on the external genitalia, labia majora or minora, vaginal vestibule, and introitus. The mucosa is often erythematous and edematous. The cervix is involved in the majority of cases and may be the only clinical feature.

 

 

 

 

 

 

 

Recurrent herpes genitalis

HSV-2 genital herpes can cause frequent recurrence with a prodrome of tenderness, burning, or pain at the site of eruption. Episodic anti-viral therapy should be taken before the vesicular eruption occurs if possible. Women often suffer from more painful recurrences and more complications than men. HSV-1 genital herpes may recur much less frequently and may cause non-painful vesicular outbreaks.

 

 

Herpes keratoconjunctivitis

Herpes keratoconjunctivitis is a serious infection of the eye that can lead to blindness. Transmission occurs through direct contact or by contact with saliva, but herpes keratoconjunctivitis is mainly found in immunocompromised individuals (Dynamed, 2011). HSV keratitis may present with pain, photophobia, blurred vision, tearing, gritty sensation, and redness. A history of prior episodes may exist if the patient suffers from recurrent disease. This is significant as patients with ocular HSV who have had previous stromal involvement are at an increased risk for stromal keratitis. Patients with epithelial keratitis only, do not have an increased rate of recurrent HSV disease. (Wang et al. Nov 2010). Patients often lose corneal sensation, which can be detected by checking for corneal reflex with a thin, wisp of tissue paper. The use of fluorescein stain and an ultraviolet light will reveal the classic dendritic ulcer on the cornea. For a good image of this and other non-genital herpes see Usatine et al. 2010.

 

Herpes encephalitis

Herpes encephalitis, although rare, is a common cause of fatal sporadic encephalitis. It is usually caused by HSV-2 in neonates, but HSV-1 is the cause in all other populations (infants over three months of age through to adulthood). Only 30% of cases are due to primary infection, with the remaining 70% from latent infection (Dynamed Herpes Encephalitis, 2011). There are no specific symptoms to distinguish herpes encephalitis from other causes; therefore, the investigational work-up is important. Common symptoms include:

• fever
• headache
• malaise, and nausea
• behavioural changes, confusion, and delirium

On exam, patients often present with:

• fever
• altered level of consciousness or seizures
• dysphasia, ataxia, hemiparesis, cranial nerve defects, visual field loss
• potentially meningeal signs (meningismus is uncommon)
• papilledema

In most cases, necrosis of the temporal lobe is the cause of the common clinical manifestations.

 

 

Neonatal herpes

Prenatal and postnatal acquired herpes can be categorized into one of three groups:

• localized to the skin, eyes, or mouth
• encephalitis with or without skin/eye/mouth involvement
• disseminated herpes that involves multiple organs, which may include the central nervous system, lungs, liver, adrenals, skin, eyes or mouth.

Apart from the typical vesicular lesions, in neonatal encephalitis or disseminated herpes, the infant can present with non-specific signs such as lethargy, failure to feed, irritability, or fever. Complications of neonatal herpes can include seizures, learning difficulties, blindness, psychomotor retardation, spasticity, and death.

 

Congenital herpes contracted in utero (4%), can result in microcephaly, hydrocephalus, chorioretinitis and vesicular skin lesions, and these babies are often born prematurely and with subsequent low birth weight (Rudnick et al. 2002).

 

 

 

 

 

 

Diagnosis

In the absence of sophisticated diagnostic equipment, the Tzanck (Giemsa) test can be used. It is 85-95% specific, but less than 50% sensitive. It will also be positive in the presence of varicella zoster virus. For a brief outline on how to complete this test see the Family Practice Notebook.

 

 

Herpes labialis and genitalis

Viral culture remains the most commonly used method for diagnosis.

1. First, clean the area with an alcohol swab. 
2. Lance the vesicle with a fine gauge sterile needle (eg/ 27G) to allow collection of the fluid on a sterile cotton tip. 
3. Immediately place the swab into the viral transport medium for transfer to the laboratory.  

Viral cultures have a low sensitivity of only 50%, therefore a negative result does not rule out infection. Polymerase chain reaction (PCR) is more sensitive and specific than viral culture alone, and can be used to determine the type of HSV infection. A viral culture with typing by PCR is the recommended diagnostic testing. Serology or immunofluoresence staining can also be used if available.

For genital lesions, consider syphilis and chancroid as other possible infectious causes, or consider drug eruptions and Behcet’s disease as non-infectious causes.

 

Herpes keratoconjunctivitis

Diagnosis of HSV keratitis is usually clinical with recognition of the typical dendritic ulcer (with fluorescein staining and ultraviolet light) that has branching with terminal bulbs, along with swollen epithelial borders that contain the virus. If in doubt, similar tests as for mucocutaneous infections can be completed. Consider Herpes Zoster, corneal abrasions or erosions, and bacterial or fungal keratitis as an alternative cause of this presentation.

 

Herpes encephalitis

Cerebral spinal fluid (CSF) collection should be completed after ruling out a space-occupying lesion. The CSF should be sent for PCR assay as it is the only definitive diagnostic method and is highly sensitive and specific for detecting HSV infection.

 

Neonatal herpes

Diagnosis of neonatal herpes is challenging and a high index of suspicion is imperative. Consider this in any infant up to one month old with fever, lethargy, poor feeding, or seizure, or in infants up to 8 weeks old with a vesicular rash. In the presence of the vesicular rash, a viral culture should be obtained, but empiric treatment with acyclovir should be started while waiting for the results. The full work-up for an infant with possible neonatal herpes includes:

• Complete blood count, including differential;
• Liver transaminases, total and direct bilirubin, ammonia, blood urea nitrogen (BUN), and creatinine ;
• HSV DNA PCR of the blood;
• Cerebrospinal fluid cell count, glucose, protein, viral culture, and HSV DNA PCR;
• Swabs/scrapings of skin or mucous membrane lesions for HSV direct immunofluorescence assay and viral culture;
• Swabs of the eye/conjunctivae, oropharynx, and stool/rectum for viral culture;
• Viral cultures of other specimens as indicated;
• Evaluation for bacterial and/or metabolic disease as suggested by the clinical scenario (Uptodate - Neonatal herpes simplex virus infection: Clinical features and diagnosis).

There is a long list of differentials in infants who present with non-specific symptoms, including bacterial, other viral or traumatic causes.

return to top

 

 

 

Treatments

Herpes labialis

1. Educate the patient on the highly infectious nature of herpes simplex and that transmission can occur through direct contact or with saliva whether the patient is currently experiencing an outbreak or not. 
2. Oral episodic treatment for primary or recurrent outbreak can be used to decrease the severity and length of the outbreak. Acyclovir and valacyclovir are most commonly used. 
3. Topical therapy with acyclovir, penciclovir, or docosanol cream can also be used; however, studies have shown that they are less effective than the oral treatment. 
4. In immunocompromised patients or in patients with frequent outbreaks, chronic suppressive therapy with daily acyclovir or valacyclovir can be used to prevent recurrences (Dynamed – Herpes labialis).

 

Herpes genitalis

1. Educate the patient on risk of recurrence and transmission. 
2. Treatment is similar to that for herpes labialis, although chronic suppressive therapy is more commonly used with herpes genitalis. 
3. For an outline of the preferred treatment regimens for first clinical episode, episodic treatment, and chronic suppressive therapy, please see the Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guideline 2010.

 

Herpes keratoconjunctivitis

1. Treatment should be supervised by an ophthalmologist. 
2. The drug of choice is trifluridine (Viroptic) 1% solution to treat and re-epithelialize the cornea. 
3. Topical acyclovir can also be used, where available, although there is some resistance in immunocompromised individuals. 
4. Topical steroids are contraindicated (Dynamed – Herpes keratoconjunctivitis 2011).

 

Herpes Encephalitis

1. Admit patient (to ICU where available) with a cardiac monitor. 
2. Ideally, an intracranial pressure transducer should be used if there is a moderate-to-severe increase in intracranial pressure. 
3. Treatment includes acyclovir IV.
4. Phenobarbital can be used to prevent convulsions. 
5. To decrease intracranial pressure in severe cerebral edema, dexamethasone, mannitol, and lasix can be used.

 

Neonatal Herpes

Without treatment, 80% of neonatal infants with HSV infection will die; this can be a greater concern in underdeveloped countries where treatment is less available (Looker et al. WHO, 2008). Treatments include:

1. Airway, breathing, circulation. 
2. Monitor for seizures and increased intracranial pressure.
3. Antiviral therapy with acyclovir IV every 8 hrs should be initiated. 
4. Monitor white blood cell count regularly as high doses of acyclovir can cause neutropenia 
5. Treatment for 14 days is usually sufficient in infants with disease limited to their skin, eyes, and mouth. With disseminated disease or central nervous system involvement, treatment should be for 21 days. For infants with recurrent cutaneous herpes symptoms, suppressive therapy with acyclovir for weeks to months can be used. 
6. Follow-up with these infants in 4-6 weeks. 
7. If ophthalmologic involvement, monitor for keratitis.

 return to top 

 

 

 

Resources and References

FREE RESOURCES

Corey et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11.

Looker et al. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. World Health Organization. 2008 Oct; 86(10): 737-816. 

Rudnick et al. Neonatal Herpes Simplex Virus Infections. Am Fam Physician. 2002 Mar 15;65(6):1138-1142.

Salvalggio et al. Herpes Simplex. eMedicine. 2010 Dec. Obtained on January 2, 2012

Smith JS, Robinson NJ. "Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review". J. Infect. Dis. 2002; 186 Suppl 1: S3–28.

Tzanck Smear. Family Practice Notebook.com

Usatine et al. Nongenital Herpes Simplex Virus. Am Fam Physician. 2010 Nov 1;82(9):1075-1082.

Wang et al. Ophthalmologic Manifestations of Herpes Simplex Keratitis Clinical Presentation. eMedicine. Updated Nov 2010.

 

OTHER REFERENCES USED

Dynamed – Herpes Genitalis (updated Oct 2011), Herpes Labialis (updated May 2011), Herpes Keratoconjunctivitis (updated Sept 2011), Herpes Encephalitis (updated Dec 2011), Neonatal Herpes (updated Nov 2011).

MD Consult – First Consult – “Herpes Simplex”

Neonatal herpes simplex virus infection: Clinical features and diagnosis. Uptodate. Obtained on January 2, 2012. 

  return to top

 

 

 

 

Topic Development

authors: Lindsey Sutherland, Jan 2012

reviewers: Dr. Tahmeena Ali, Jan 2012

 return to top