054 – Herpes simplex

Herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections (cold sore, fever blister, herpes gladiatorum, scrum pox, herpetic whitlow, herpes progenitalis) are common worldwide, usually affecting the orolabial and genital regions respectively, although any skin area may be affected.

Infection is acquired through contact with contaminated saliva or other body fluids during periods of viral shedding. The virus establishes lifelong latency in the dorsal root ganglia. Clinical disease occurs with reactivation (spontaneously or with trauma, UV exposure, fever, or immunosuppression) of the latent virus, which travels from the nerve root to innervated skin regions.

Primary infection denotes the initial inoculation episode, which may be subclinical or cause significant disease, usually in children. Recurrent disease describes reactivation episodes, which occur in 30–50% of oral HSV and 95% of genital HSV infections. An individual may be co-infected with more than one type of HSV and in more than one location. HSV acquisition at a new site in a previously infected person is designated non-primary, first episode infection.

Ninety percent of adults are antibody positive to HSV-1. HSV-2 prevalence is lower, affecting almost a quarter of the US population. Symptoms of primary disease are usually more severe than recurrent disease and depend upon the site of inoculation. Herpetic gingivostomatitis (usually HSV-1) presents with fever, malaise, bleeding, painful gums, pain upon eating, and sometimes pharyngitis and foul breath. Localized adenopathy is common with primary infection. Disease occurs 3–7 days after exposure; recovery from a primary episode usually occurs in 2–6 weeks.

Recurrent disease usually lacks constitutional symptoms. Itching, burning, or pain often precedes the skin lesions. Disseminated infection and pneumonitis may occur in the immunocompromised. Other complications of HSV infection include bacterial superinfection, radiculoneuropathy, erythema multiforme, aseptic meningitis and encephalitis, hepatitis, Bell palsy, and eczema herpeticum in patients with atopy.

HSV infection in HIV-infected patients and other immunodeficiency states with T-cell defects is common and often presents with more severe and chronic disease. Chronic non-healing, painful ulcers may occur. Others at risk include marrow and solid organ transplant patients and patients with lymphoma and leukemia.

Grouped, umbilicated vesicles and a history of recurrent "flares" should alert one to the possibility of this diagnosis over cellulitis.

Groups of umbilicated vesicles, usually on the perioral skin or mucosa. The vesicles may have an erythematous base. In moist areas, the vesicles quickly rupture, leaving behind painful ulcerations. Vesicles on the skin also eventually rupture, leaving a crusted ulcer.

A history of recurring localized skin process, where vesicles, erosions, or vesiculopustules recur at the same body location, should force consideration of recurrent HSV infection.

Facial:
Differentiate from zoster, which also presents with umbilicated vesicles.
Molluscum contagiosum
Fixed drug eruption
Insect bites
Candidiasis
Contact dermatitis

Orolabial:
Herpangina
Aphthous stomatitis
Erythema multiforme
Drug-induced mucositis
Impetigo
Oral erosive lichen planus
Hand-foot-and-mouth disease
Behçet's syndrome

This diagnosis can often be made based on a careful history and characteristic physical exam findings. Confirmatory studies include:

• Tzanck prep of a vesicle base looking for multinucleated giant cells.
• Viral culture.
• PCR for HSV DNA.
• Skin biopsy.
• Bacterial culture if there is evidence of impetiginization.
• Direct fluorescence antigen testing (DFA) is a rapid (less than 24 hour) and sensitive test for HSV-1, HSV-2, and VZV. This test is performed by vigorously scraping the base of a vesicle with a sterile cotton-tipped swab or 15 blade and smearing the cells onto a glass slide from a DFA kit. The slide is then fixed (usually contained in a kit) and sent for immunofluorescence analysis. Individual slides must be sent for each virus suspected. Slides can be stored at room temperature for 24 hours after fixation, if needed.

In severe cases of herpetic gingivostomatitis, the patient may be unable to take oral fluids and may need intravenous fluids and pain relief with narcotics.

If episodes are frequent (6 or more per year) and severe, consider prophylactic therapy with oral acyclovir. Episodic oral therapy can be used in the patient who experiences tingling before the onset of vesicles. These patients should carry with them at least one oral dose and initiate therapy with the onset of symptoms.

Advise patients about the risk of autoinoculation (ie, of the eye), and encourage proper handwashing techniques.

UV protection may help to reduce the frequency of viral reactivation in herpes labialis.

Precautions: Standard and Contact (Isolate patient, wear gloves and a gown, limit patient transport, and avoid sharing patient-care equipment.)

Pain control is important in cases of herpetic gingivostomatitis:

• 2% viscous lidocaine, swish and spit out 5 mL 4–5 times daily as needed. This can also be mixed with equal volumes of Kaopectate® (or Maalox®) and Benadryl® used in a similar manner.
• 1.0% dyclonine HCL in aqueous solution, swish and spit out 5 ml 4–5 times a day.
• Ice chips and popsicles are helpful for relieving mouth pain and providing some hydration.
• Non-steroidal anti-inflammatory agents or acetaminophen are often sufficient for pain and fever.

Treatment with acyclovir or its prodrugs (valacyclovir or famciclovir) work best to target the virus. Topical antiviral agents may be useful during the primary episode to decrease viral shedding and patient discomfort, but they are generally less helpful in the management of recurrent outbreaks of HSV. Some topical agents include:

• Acyclovir 5% cream applied 6 times daily for 7 days
• Penciclovir 1% cream applied every 2 hours while awake for 4–5 days
• Docosanol 10% cream applied 5 times daily for 5–10 days
• Cidofovir cream or gel applied once daily for acyclovir-resistant localized HSV

CDC-Recommended Regimens - First Clinical Episode
Systemic antiviral drugs can partially control the signs and symptoms of HSV episodes when used to treat first clinical and recurrent episodes or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials have indicated that 3 antiviral medications provide clinical benefit for HSV: acyclovir, valacyclovir, and famciclovir.

Acyclovir 400 mg orally 3 times daily for 7–10 days
OR
Acyclovir 200 mg orally 5 times daily for 7–10 days
OR
Famciclovir 250 mg orally 3 times daily for 7–10 days
OR
Valacyclovir 1 g orally twice daily for 7–10 days

CDC-Recommended Regimens – Suppressive Therapy
Suppressive therapy reduces the frequency of HSV recurrences by 70–80% in patients who have frequent recurrences (6 or more per year), and many patients report no symptomatic outbreaks. This is most often applied in cases of genital HSV. Treatment is also effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year. Quality of life is often improved in patients with frequent recurrences who receive suppressive therapy, compared with episodic treatment.

Acyclovir 400 mg orally twice daily
OR
Famciclovir 250 mg orally twice daily
OR
Valacyclovir 500 mg orally once daily
OR
Valacyclovir 1.0 g orally once daily

CDC-Recommended Regimens – Episodic Therapy
Effective episodic treatment of recurrent HSV requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The patient should be provided with a supply of drug or a prescription for the medication with instructions to immediately initiate treatment when symptoms begin.

Acyclovir 400 mg orally 3 times daily for 5 days
OR
Acyclovir 800 mg orally twice daily for 5 days
OR
Acyclovir 800 mg orally 3 times daily for 2 days
OR
Famciclovir 125 mg orally twice daily for 5 days
OR
Famciclovir 1000 mg orally twice daily for 1 day
OR
Valacyclovir 500 mg orally twice daily for 3 days
OR
Valacyclovir 1.0 g orally once daily for 5 days

CDC-Recommended Regimens – Suppressive Therapy in HIV-Infected Persons
Acyclovir 400–800 mg orally 2–3 times daily
OR
Famciclovir 500 mg orally twice daily
OR
Valacyclovir 500 mg orally twice daily

CDC-Recommended Regimens – Episodic Therapy in HIV-Infected Persons
Acyclovir 400 mg orally 3 times daily for 5–10 days
OR
Famciclovir 500 mg orally twice daily for 5–10 days
OR
Valacyclovir 1.0 grams orally twice daily for 5–10 days

Acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients in the doses recommended for treatment of HSV. For severe HSV disease, initiating therapy with acyclovir 5–10 mg/kg body weight IV every 8 hours might be necessary.

Antistaphylococcal antibiotics (eg, topical mupirocin) may be used in the prevention or treatment of superficial impetiginization.

Some patients find that outbreaks are triggered by sunlight or sunburn. In these patients, encourage the use of sun-protective clothing (eg, hats), sunscreens, and sun avoidance.

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Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007 Nov;57(5):737-63; quiz 764-6. PubMed Id: 17939933

Lebrun-Vignes B, Bouzamondo A, Dupuy A, Guillaume JC, Lechat P, Chosidow O. A meta-analysis to assess the efficacy of oral antiviral treatment to prevent genital herpes outbreaks. J Am Acad Dermatol. 2007 Aug;57(2):238-46. PubMed Id: 17416440

Lingappa JR, Celum C. Clinical and therapeutic issues for herpes simplex virus-2 and HIV co-infection. Drugs. 2007;67(2):155-74. PubMed Id: 17284082

Ouedraogo A, Nagot N, Vergne L, Konate I, Weiss HA, Defer MC, Foulongne V, Sanon A, Andonaba JB, Segondy M, Mayaud P, Van de Perre P. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS. 2006 Nov 28;20(18):2305-13. PubMed Id: 17117016

Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, Douglas JM, Paavonen J, Morrow RA, Beutner KR, Stratchounsky LS, Mertz G, Keene ON, Watson HA, Tait D, Vargas-Cortes M, Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004 Jan 1;350(1):11-20. PubMed Id: 14702423

Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997 Oct 16;337(16):1105-11. PubMed Id: 9329932

Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis. 1997 Sep;24(8):481-6. PubMed Id: 9293612

Appearance
No Acute Distress
Patient Appears Ill

Body Location
Arm
Buttocks
Cheek
Crural or Inguinal Fold
Face
Female Genital
Fingers
Hand or Fingers
Labia Majora
Labia Minora/Vestibule
Lips
Male Genital
Mouth
Palm
Penis
Perianal-Anus
Perineum
Periungual Fingers
Sacral Region of Back
Scrotum
Vaginal Opening

Configuration
Grouped

Distribution
Unilateral

Lesion
Buccal Mucosa Bullae
Buccal Mucosa Ulcer
Buccal Mucosa Vesicle
Crust
Erosion
Gingival-Alveolar Mucosa Erosion
Hard Palate Erosion
Lip Mucosa Erosion
Lip Mucosa Hemorrhagic Crust
Lip Mucosa Vesicle
Soft Palate Erosion
Soft Palate Vesicle
Tense Vesicle
Tongue Erosion
Tongue Vesicle
Ulcer
Umbilicated Vesicle

Medications
Immunosuppressive

Occupations
Military

Signs and Symptoms
Drooling
Dysphagia (Difficulty Swallowing, Painful Swallowing)
Fever (Febrile)
Lymphadenopathy
Mouth Pain
No Fever (Afebrile, Apyrexial)
Pain or Itch Precede Rash by Days
Pruritus (Itching)
Sore Throat

Social History
Sporting Activity
Weightlifting
Wrestler

Temporal
Developed Acutely Over Days to Weeks
Developed Rapidly in Minutes or Hours
Recurring Episodes or Relapses

Medical History
Acquired Immune Deficiency Syndrome (AIDS)
Human Immunodeficiency Virus (HIV) Disease
Immunosuppression/Immunocompromised