AUTHOR INFORMATION

Section 1 of 12

Authored by Rahul Sharma, MD, MBA, Instructor in Medicine and Faculty Member, Emergency Medicine Residency, Weill Medical College of Cornell University; Attending Physician, Department of Emergency Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center

Coauthored by Lawrence C Brilliant, MD, Clinical Assistant Professor, Department of Primary Care and Community Services, Hahnemann University; Attending Physician, Department of Emergency Med, Doylestown Hospital

Rahul Sharma, MD, MBA, is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and American Medical Association

Edited by Robin R Hemphill, MD, MPH, Associate Professor, Director, Disaster Preparedness, Department of Emergency Medicine, Vanderbilt University Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Eric L Weiss, MD, DTM&H, Director of Stanford Travel Medicine, Medical Director of Stanford Lifeflight, Assistant Professor, Departments of Emergency Medicine and Infectious Diseases, Stanford University School of Medicine; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Steven C Dronen, MD, FAAEM, Director of Emergency Services, Director of Chest Pain Center, Department of Emergency Medicine, Ft Sanders Sevier Medical Center

Author's Email:	Rahul Sharma, MD, MBA
Editor's Email:	Robin R Hemphill, MD, MPH

eMedicine Journal, June 1 2006, VOLUME 7, Number 6

INTRODUCTION

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Background: The herpes simplex viruses comprise 2 distinct types of DNA viruses, HSV-1 and HSV-2. HSV-1 causes oral lesions in approximately 80% of cases and genital lesions in 20% of cases. The reverse is true for HSV-2, which causes genital lesions in 80% and oral lesions in 20%. About 80% of the general adult population has serologic infection with HSV-1 with only about 30% of these individuals having clinically significant outbreaks. Approximately 20% of the adult population in the United States is seropositive for HSV-2. It has been estimated that the indirect and direct costs of incident HSV genital infection in the United States are presently approximately $1.8 billion and expected to be greater than $2.7 billion by the year 2015. Herpes viruses cause a wide range of diseases, including the following:

• Gingivostomatitis

• Keratoconjunctivitis

• Encephalitis

• Genital disease

• Newborn infection

Primary infection

Primary infections usually are mild and in many cases asymptomatic. Patients who are immunocompromised may develop severe infections involving multiple organ systems. Immunocompetent individuals also may have severe primary infections.

Latency and recurrence

After the patient begins to produce antibodies, the infection becomes latent in the sensory ganglia. HSV-1 infection remains latent in the trigeminal ganglia, and HSV-2 in the sacral ganglia. The viruses become reactivated secondary to certain stimuli, including fever, physical or emotional stress, ultraviolet light exposure, and axonal injury.

Recurrent infections tend to be less severe because of existing cellular and humoral immunity from prior exposures. Infection by HSV requires a break in the skin’s barrier; intact skin is resistant to the virus.

Pathophysiology: HSV-1 infections are spread via respiratory droplets or direct exposure to infected saliva. HSV-2 usually is transmitted via genital contact. The contact must involve mucous membranes or open or damaged skin.

Herpes viruses cause cytolytic infections; therefore, pathologic changes are due to cell necrosis as well as inflammatory changes. Fluid accumulates between the dermis and the epidermal skin layers and causes vesicle formation. The fluid then is absorbed, scabs are formed, and healing is completed without evidence of scarring. Shallow ulcers form after the vesicles rupture on mucous membranes.

The virus travels from the site of infection in the skin or mucosa to the sensory dorsal root and remains latent until a recurrent outbreak. Outbreaks are usually due to some sort of stress including ultraviolet radiation, trauma, emotional or psychological stress, or immunosuppression.

Frequency:

• In the US: Approximately 80% of adults have antibodies to HSV-1, whereas antibodies to HSV-2 are found in approximately 20% of the population.

• The incidence of genital herpes has been estimated to be 500,000-1,000,000 cases per year with a prevalence of 40-60 million affected individuals.

• In sexually transmitted disease (STD) clinics, HSV-2 seropositivity approaches 40-50%.

• Encephalitis develops in 1 per 250,000-500,000 patients per year.

• Neonatal HSV develops in 1 per 2,000-10,000 live births per year. The risk of maternal transmission is increased if vaginal delivery occurs during the mother's primary infection. Approximately 70% of cases of neonatal HSV occur when the mother is asymptomatically shedding virus near time of delivery.

• Approximately 90% of HIV-positive individuals are seropositive for HSV-1, and about 77% of HIV-positive individuals are seropositive for HSV-2.

• Internationally: Greater than one third the world's population has recurrent clinical HSV infections. Reportedly, 13-40% of the world's population is seropositive for HSV-2 and 56-85% is seropositive for HSV-1, varying by country.

Mortality/Morbidity: Most cases of herpetic infection are limited to patient irritation and discomfort.

• Infection occasionally may become life threatening.

• Patients who are immunocompromised are at increased risk of developing severe HSV infections.

• HSV-1 is a common cause of fatal encephalitis in the US. Mortality rate for encephalitis is 60-80%. Fewer than 10% of patients are left without significant neurologic sequelae.

• Keratoconjunctivitis may be caused by HSV-1. It is second only to trauma as a cause of corneal blindness in the US.

Race: HSV-2 antibodies are present in approximately 20% of Caucasian adults and 65% of African American adults. Some experts consider nonwhite race as a risk factor to contract genital HSV-2.

Sex: Men are 20% more likely to develop recurrences of HSV-2 than are women.

Age:

• Highest incidence of HSV-1 occurs in children aged 6 months to 3 years.

• HSV-2 most commonly occurs in those aged 18-25 years.

CLINICAL

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History: Infection begins a chronological development of symptoms. First, the prodrome occurs, and lesions then appear along with constitutional signs and symptoms. The lesions coalesce, and tender bilateral lymphadenopathy develops. Lesions usually heal over the next several weeks. Lesions usually are vesicular or ulcerative on an erythematous base and are very painful.

• Many primary infections are asymptomatic. However, when primary infections are symptomatic, they are usually more severe than recurrent infections.

• Recurrent lesions are common.

• Patients may give a history that includes the following:

• Occupational exposure
  • Herpetic whitlow, found in health care workers (especially medical or dental)

  • Herpes gladiatorum on bodies of wrestlers

• Previous history of herpetic diseases

• Apparently undiagnosed episodes

• Immune status

• HIV

• Malnourishment

• Hematological malignancies

• Bone marrow

• Renal transplant

• Cardiac transplant

• Neurologic symptoms

• Headache

• Confusion

• Fever

• Lesions

• Location varies

• May be very painful

• Tenesmus, itching with anal/perianal lesions

• Dysuria with genital lesions

• Sore throat with oral lesions

• Constitutional symptoms (usually present with development of herpes lesions)

• Anorexia

• General malaise

• Prodromal symptoms (present in advance of herpes lesions)

• Burning

• Itching

Physical: Physical examination findings vary depending on location of the lesions.

• General findings

• Lesions usually are vesicular or ulcerative on an erythematous base and are very painful (see Picture 1).

• Lesions coalesce and then heal over the next several weeks.

• Tender bilateral lymphadenopathy occurs with the lesions.

• Skin infections (HSV-1 or HSV-2)

• Herpetic whitlow or paronychia on the fingers of health care workers (not to be confused with abscess). This is usually is due to infection with HSV-1, but HSV-2 infections may be seen with digital-genital contact.

• Herpes gladiatorum on the bodies of wrestlers and other sports that involve close physical contact. It has been estimated that in Division I National Collegiate Athletic Association (NCAA) wrestling, the incidence of herpes gladiatorum can be as high as 20-40%.

• Oropharyngeal disease

• Gingivostomatitis (herpes labialis on the lips; see Picture 2)

• Submandibular lymphadenopathy

• Fever

• Genital herpes

• Painful vesicular or ulcerative lesions may appear similar to chancroid or syphilis (see Picture 3)

• Inguinal lymphadenopathy

• Keratoconjunctivitis

• Dendritic keratitis found with slit lamp (see Picture 5)

• Corneal ulcers

• Vesicles on eyelids

• Neurologic

• New psychiatric symptoms (indicative of encephalitis)
  • Confusion

  • Seizures

  • Meningeal signs - Recurrent lymphocytic meningitis (benign form of meningitis/encephalitis that may occur during primary HSV-2 infection)

• Bell palsy (possible relationship with HSV-1)

• Anal/perianal involvement

• Discharge

• Vesicles

• Ulcerations

• Inguinal adenopathy

Causes:

• HSV-1 - Transmitted through direct contact with infected saliva or direct contact with contaminated utensils

• HSV-2 - Usually acquired as an STD

• Maternal-fetal transmission

• Recurrent disease (reactivation) due to certain stimuli

• Fever

• Physical or emotional stress

• Ultraviolet light exposure

• Axonal injury

DIFFERENTIALS

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Chancroid
Erythema Multiforme
Herpes Zoster
Pediatrics, Hand-Foot-and-Mouth Disease
Pediatrics, Meningitis and Encephalitis
Pediatrics, Pharyngitis
Pharyngitis
Proctitis
Syphilis
Urethritis, Male

Other Problems to be Considered:

Aphthous stomatitis

WORKUP

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Lab Studies:

• Scrapings from suspected lesions (Tzanck smear). This is not a very reliable screening test, with a sensitivity reported around 65%, and it also does not differentiate between the type of HSV present.

• Multinucleated giant cells (see Picture 4)

• Intranuclear inclusions

• Viral culture from skin vesicles (more sensitive that Tzanck smear but dependent on duration of viral shedding)

• Monoclonal antibody testing

• Serology

• Cerebrospinal fluid (CSF) analysis for lymphocytic pleocytosis

• Bloody CSF

• Polymerase chain reaction (PCR) detects HSV DNA

Imaging Studies:

• CT scan and MRI for differentiation of encephalitis from other entities

Procedures:

• Slit-lamp examination for dendritic keratitis with ocular involvement

• Lumbar puncture, if concerned about encephalitis

• Brain biopsy, if encephalitis is considered

TREATMENT

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Emergency Department Care: ED care consists of diagnosis and appropriate treatment. Most patients may be treated in the outpatient setting. Identification of patients that need inpatient treatment (ie, encephalitis) and initiation of antiviral and supportive therapy is imperative.

Consultations:

• Ophthalmologist for keratoconjunctivitis

• Obstetrician for active genital herpes in a near-term pregnancy

• Outpatient dermatologist for differentiation of skin infections

• Infectious disease specialist for disseminated disease and encephalitis

MEDICATION

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Antiviral drugs with activity against viral DNA synthesis have been effective against HSV infections. These drugs inhibit virus replication and may suppress clinical manifestations but are not a cure for the disease. Since HSV remains latent in sensory ganglia, the rates of relapse are similar in treated and untreated patients.

Acyclovir (Zovirax) provides initial, recurrent, and suppressive therapy for genital HSV. It is effective for mucocutaneous HSV in an immunocompromised host as well as HSV encephalitis. Little evidence supports the routine use of acyclovir for primary oral-labial HSV. Oral acyclovir has been shown to be effective in suppressing herpes labialis in patients with immunocompromise who frequently have recurrent infections. One study reported that oral acyclovir reduced duration of pain by 36% and time to loss of crust by 27%. Begin use during the prodromal period.

Administer famciclovir (Famvir) and valacyclovir (Valtrex) for recurrent episodes of genital HSV. Herpes simplex keratoconjunctivitis is treated with topical 1% trifluridine (Viroptic).

Use pain medication as needed.

Drug Category: Antiviral agents -- The goals in use of antivirals are to (1) shorten the clinical course, (2) prevent complications, (3) prevent the development of latency and/or subsequent recurrences, (4) decrease transmission, and (5) eliminate established latency.

Drug Name	Acyclovir (Zovirax) -- DOC; reduces duration of symptomatic lesions. Indicated for patients presenting within 48 h of rash onset. Patients on acyclovir experience less pain and faster resolution of cutaneous lesions.
Adult Dose	Genital HSV First episode: 200 mg PO 5 times/d for 10 d or 400 mg PO tid for 7-10 d (equally effective) Recurrent episodes: 400 mg PO tid for 5 d Suppressive therapy: 400 mg PO bid Mucocutaneous HSV in immunocompromised host Mild: 200-400 mg 5 times/d for 10 d Severe: 5 mg/kg IV q8h for 7-10 d or 400 mg PO 5 times/d for 14-21 d Encephalitis: 10 mg/kg IV q8h for 14-21 d Herpetic whitlow: 400 mg PO tid for 10 d Frequently recurrent herpes labialis: 400 mg PO bid for 4 mo
Pediatric Dose	Immunocompromised: 250-600 mg/m2/dose PO 4-5 times/d for 7-10 d HSV encephalitis: 10 mg/kg/dose IV or 500 mg/m2/dose q8h
Contraindications	Documented hypersensitivity
Interactions	Probenecid or zidovudine prolongs half-life and increases CNS toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal failure or with coadministration of other nephrotoxic drugs; some adverse effects include nausea, vomiting, rash, deposition in renal tubules, and CNS symptoms

Drug Name	Famciclovir (Famvir) -- Prodrug that, when biotransformed into active metabolite penciclovir, may inhibit viral DNA synthesis/replication. Useful for recurrent episodes of genital HSV.
Adult Dose	125-250 mg PO bid/tid for 5 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid or cimetidine prolongs half-life (may increase toxicity); increases bioavailability of digoxin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure or coadministration of nephrotoxic drugs

Drug Name	Valacyclovir (Valtrex) -- Prodrug that is rapidly converted to acyclovir before exerting its antiviral activity. Valacyclovir is more expensive but has more convenient dosing regimen than acyclovir. Useful for recurrent episodes of genital HSV.
Adult Dose	500-1000 mg PO bid for 5-10 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid, zidovudine, or cimetidine prolongs half-life and increases CNS toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure and coadministration of nephrotoxic drugs; associated with onset of hemolytic uremic syndrome

Drug Name	1% Trifluridine (Viroptic) -- Replaces thymidine in viral DNA, resulting in production of defective proteins and thus inhibiting viral replication. Useful in treatment of keratoconjunctivitis.
Adult Dose	1 gtt q2h until corneal ulcer has re-epithelialized completely; not to exceed 9 gtt/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause mild local transient irritation of conjunctivae and cornea upon instillation

Drug Name	Docosanol cream (Abreva) -- Prevents viral entry and replication at cellular level. Use at first sign of cold sore or fever blister.
Adult Dose	Apply 5 times/d to affected area on lips or face and continue application until healed
Pediatric Dose	<12 years age: Not established >12 years age : Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	For external use only; not to be used for inside of mouth or near eyes; may cause headaches

FOLLOW-UP

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Further Inpatient Care:

• Admission is necessary in the following instances:

• Encephalitis

• Severe gingivostomatitis causing decreased ability to tolerate oral fluids

• Immunocompromised patients with severe or disseminated disease

Further Outpatient Care:

• Oral medication (see Medication): Topical acyclovir is only minimally helpful in patients with primary disease and is probably ineffective in recurrent episodes.

• Burroughs Wellcome Co maintains a registry for monitoring outcome in pregnant women exposed to acyclovir; physicians should register patients at (800) 722-9292, extension 58465.

Deterrence/Prevention:

• HSV-2 is an STD. Patients and all sexual contacts should be tested and treated for accompanying STDs.

• Practice abstinence when lesions are present.

• Always use condoms because of the potential for asymptomatic viral shedding.

• Health care personnel (especially medical, dental) should use universal precautions (eg, gloves) to prevent herpetic whitlow.

• Experimental vaccines are currently in clinical trials.

• Use sunscreen to decrease herpes labialis recurrences.

Complications:

• Encephalitis

• Rare complication of herpetic infection

• Commonly HSV-1 (hypothesized to spread to the brain via neural routes after primary or recurrent infection)

• Neonatal infections

• Range from mild localized infection to a fatal disseminated disease

• HSV-2 usually spread via the maternal genital tract

• Congenital infections possible

• Compromised host - Progressive and disseminated disease possible

• Genital infection - Acute urinary retention

Prognosis:

• High recurrence rate for genital HSV-2 infection

• More than 85% of patients with one symptomatic episode will experience another.

• Recurrences may be frequent; 38% of the population with genital herpes have more than 6 recurrences per year; 20% have more than 10 recurrences per year.

Patient Education:

• Antiviral therapy may decrease the clinical manifestations of the disease but does not cure it.

• Initiate antiviral therapy as soon as possible after the patient notes symptoms.

• Consider prophylaxis for patients who have more than 6 recurrences per year.

• Educate patient that HSV-2 is an STD. Follow deterrence measures.

• Referral to support groups: The American Social Health Association (ASHA) operates the National Herpes Hotline (919-361-8488), which provides educational materials and counseling for patients.

• For excellent patient education resources, visit eMedicine’s Sexually Transmitted Diseases Center and Teeth and Mouth Center. Also, see eMedicine’s patient education articles Genital Herpes and Oral Herpes.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to identify active lesions at the time of labor and to perform cesarean section to decrease risk of transmission to the neonate

• Failure to refer all contacts of patients with genital HSV-2 for follow-up

• Failure to test, treat, and arrange counseling for associated STDs

• Failure to treat disseminated disease aggressively in immunocompromised patients

• Failure to diagnose herpetic keratoconjunctivitis in a patient who presents with a red eye

• Failure to suspect and diagnose meningitis or encephalitis

• Do not incise and drain herpetic whitlow

Special Concerns:

• Pregnancy and HSV disease

• Neonate and HSV disease

• Patients who are immunocompromised with HSV disease

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following cannot be used to treat recurrent episodes of genital HSV infection?

A: Acyclovir PO
B: Famciclovir PO
C: Valacyclovir PO
D: Topical trifluridine
E: Oral pain medication

The correct answer is D: Topical trifluridine is indicated for the ocular treatment of herpetic keratoconjunctivitis.

CME Question 2: What percentage of patients with one symptomatic genital HSV infection will experience another?

A: 5%
B: 10%
C: 25%
D: 50%
E: 85%

The correct answer is E: The recurrence rate of genital HSV after the initial episode is very high (85%).

Pearl Question 1 (T/F): Fever, physical or emotional stress, ultraviolet light exposure, and axonal injury can cause reactivation of HSV.

The correct answer is True: Sunscreen use can help reduce herpes labialis occurrences.

Pearl Question 2 (T/F): A dental hygienist visits the ED with multiple painful vesicular lesions on her finger. Herpetic whitlow is the likely diagnosis.

The correct answer is True: Health care personnel (especially medical and dental) should use universal precautions (eg, gloves) to prevent herpetic whitlow.

Pearl Question 3 (T/F): The diagnosis of herpetic keratoconjunctivitis is confirmed by finding diffuse punctate lesions on the cornea associated with marked conjunctival hyperemia.

The correct answer is False: Herpetic keratoconjunctivitis is characterized by a dendritic pattern on the cornea under slit-lamp examination.

Pearl Question 4 (T/F): Additional counseling should be offered to patients with genital HSV.

The correct answer is True: Genital herpes is an STD. Test and treat patients for other STDs. Advise the patient always to use condoms and to refrain from sexual intercourse during acute flares of the disease. Counseling and emotional support also are available.

PICTURES

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Caption: Picture 1. Cutaneous vesicles characteristic of herpes simples virus infection
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Caption: Picture 2. Herpes labialis
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Caption: Picture 3. Penile infection with herpes simplex virus type 2
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Caption: Picture 4. Tzanck smear showing a multinucleated giant cell
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Caption: Picture 5. Herpes simplex virus dendritic ulcer with fluorescein staining.
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BIBLIOGRAPHY

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• Benedetti J, Corey L, Ashley R: Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994 Dec 1; 121(11): 847-54[Medline].
• Clark JL, Tatum NO, Noble SL: Management of genital herpes. Am Fam Physician 1995 Jan; 51(1): 175-82, 187-8[Medline].
• Cockerell C: Diagnosis and treatment of cutaneous herpes simplex virus infections. West J Med 1996 Jun; 164(6): 518-20[Medline].
• Hill J, Roberts S: Herpes simplex virus in pregnancy: new concepts in prevention and management. Clin Perinatol 2005 Sep; 32(3): 657-70[Medline].
• Hirsch MS: Herpes simplex virus. In: GL Mandell, ed. Mandell, Douglas, and Bennet's Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone; 1995: 1336-45.
• Johnson R: Herpes gladiatorum and other skin diseases. Clin Sports Med 2004; 23(3): 473-84.
• Patel R, Rompalo A: Managing patients with genital herpes and their sexual partners. Infect Dis Clin North Am 2005 Jun; 19(2): 427-38, x[Medline].
• Rooney JF, Straus SE, Mannix ML: Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann Intern Med 1993 Feb 15; 118(4): 268-72[Medline].
• Sanford JP, Gilbert DN, Moellering RC, et al: Recommended antiviral therapy. In: Guide to Antimicrobial Therapy. 27th ed. 1997: 93-4.
• Whitley RJ, Gnann JW Jr: Acyclovir: a decade later. N Engl J Med 1992 Sep 10; 327(11): 782-9[Medline].
• Wu JJ, Pang KR, Huang DB: Advances in antiviral therapy. Dermatol Clin 2005 Apr; 23(2): 313-22[Medline].

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