Herpes Viruses

I. What every physician needs to know.

Herpes viruses are a large family of deoxyribonucleic acid (DNA) viruses known to cause latent and recurring/reactivated infections. There are eight viruses in this family known to cause human infections. They are:

Herpes simplex virus – 1 (HSV-1) (herpes labialis; oral and/or genital, HSV encephalitis);
Herpes simplex virus – 2 (HSV-2) (oral and/or genital, HSV meningitis);
Varicella zoster virus (VZV) (chickenpox and shingles);
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Epstein-Barr virus (EBV, infectious mononucleosis, Burkitt lymphoma);
Cytomegalovirus (CMV);
Roseolovirus (Herpes lymphotropic virus) (Human herpes virus 6);
Roseolovirus (Human herpes virus 7);
Kaposi’s sarcoma-associated herpes virus

For the purposes of this chapter, we will concentrate on HSV-1 and 2 which cause primarily oral and genital vesiculobullous lesions, with the mucoepithelial cell being the primary target cell.

Primary infection occurs when a patient who was previously HSV seronegative becomes inoculated with HSV after direct contact with an active lesion (or from asymptomatic shedding) as the virus gains entry through the dermis or epidermis. An outbreak of vesicular lesions on an erythematous base appears accompanied by systemic symptoms of fever, lethargy, headache, and lymphadenopathy. Primary infections can range from severe gingivostomatitis to no symptoms at all. After replicating is epithelial cells, HSV is transported into sensory neurons (typically the trigmenial ganglia with HSV-1 or the sacral ganglia with HSV-2) and establishes latency, whereby the HSV DNA exists in the nucleus of the human neuron. During times of stress, HSV can reactivate, viral components will assemble, and then are transported out of the neuron to neighboring epithelial cells, resulting in skin lesions. Even when there are no lesions visible, HSV can asymptomatically shed through mucosa and secretions and infect others.

HSV can infect the central nervous system resulting in herpes encephalitis. Herpes encephalitis is almost always due to HSV-1 in adults and is a life threatening infection associated with severe morbidity and mortality. On the contrary, HSV meningitis, which is typically caused by HSV-2 can be self-limiting. These viruses can also affect visceral organs (esophagus, lungs, liver), but these are generally seen in immunocompromised hosts.

II. Diagnostic Confirmation: Are you sure your patient has a herpes virus?

HSV infection can be confirmed with HSV PCR (polymerase chain reaction) assays, viral culture, serology, immunofluorescence, or a Tzanck preparation. Of all these methods, PCR assay is the most sensitive and specific.

Diagnosis by PCR has become the gold standard for real-time diagnosis of HSV infection, particularly in cases of HSV encephalitis, but can also be used in mucocutaneous and genital eruptions. The sensitivity for detecting HSV DNA by cerebrospinal (CSF) PCR is approximately 96 %, and the specificity is approximately 99 %.

Viral culture yields highest if collected within 24-48 hours of appearance of lesions. The vesicle should be unroofed with a sterile instrument and vesicular fluid is collected with a sterile swab and placed in viral culture medium. Recovery of the virus with this method is possible in only 7-25% of patients.

Several different serologic assays have been used to diagnose HSV. This has limited use, however, due to persistence of type-specific antibodies indefinitely. Serologic studies may be negative in early stages of an infection, and you would expect a several fold rise between acute and convalescent sera. Type specific HSV serologic testing may be helpful in diagnosing a patient with recurrent genital lesions and a negative HSV PCR or viral culture.

Direct immunofluorescent staining uses fluorescein-labeled HSV type-specific monoclonal antibodies, but again is not as sensitive as PCR.

The Tzanck smear is not utilized very frequently anymore given the low specificity and sensitivity. In brief, a slide prepared at the bedside, where lesion scrapings are fixed with ethanol or methanol and stained with Giemsa or Wright stain. When prepared properly, these show multinucleated giant cells which indicate infection with either HSV or vesicular stomatitis virus (VSV).

A. History Part I: Pattern Recognition:

Primary HSV-1 presents with fairly sudden onset of the classic vesicular skin lesions on an erythematous base. The incubation period is 2-12 days. Primary infection can present with generalized symptoms of fever and malaise as well. The painful lesions last for 10-14 days and are grouped. Primary infection can also be completely asymptomatic. The virus can remain in a latent phase, living in nerve cell bodies of ganglion neurons, and can reactivate at any given time. Recurrent infection with HSV is not usually accompanied by systemic symptoms, but patients can have localized lymphadenopathy.

Genital HSV is generally HSV-2 but can be HSV-1. Patients with primary infection present with painful vesicular or ulcerative lesions, tender localized lymphadenopathy, dysuria, fever, itching, and headache. The incubation period after exposure is 2-12 days. Recurrent infection can present with milder symptoms. There can be a prodrome of tingling or pain in the buttocks, legs, or hips. Lesions are present for approximately 10 days (as opposed to 19 in primary disease). Most patients with genital HSV are unaware they have an infection.

HSV encephalitis presents with fever, headache, focal neurologic deficits (hemiparesis, aphasia), personality changes, confusion, and seizures. HSV encephalitis is diagnosed with a positive HSV DNA CSF PCR. For patients with suspected HSV encephalitis, treatment with acyclovir 10 milligram/kilogram (mg/kg) intravenous (IV) every 8 hours for 14-21 days should be initiated immediately. Approximately 70% of patients will expire with untreated HSV encephalitis. Even with appropriate treatment, mortality can reach 20% and survivors often have significant neurological deficits and neurobehavioral complications.

B. History Part 2: Prevalence:

In a 2004 study, HSV-1 was found to be present in over 57% of Americans, however, this number is thought to be closer to 80% (and 85% worldwide). The prevalence of HSV-2 varies based on age, gender, ethnicity, and sexual activity. On average, the seroprevalence in the United States is around 15.5% (2010). Interestingly, most patients with genital herpes were unaware of their infection and nearly 90% of HSV-2 seropositive patients stated they were never told by a clinician they had genital herpes. Prevalence of genital herpes is higher in women, African-Americans, and sexually promiscuous patients.

C. History Part 3: Competing diagnoses that can mimic herpes viruses.

Not too many diseases cause the dermatomal distribution that is seen with herpes virus infections.

Differential diagnosis for HSV-1 and oral lesions includes recurrent aphthous ulcers, aphthous stomatitis, syphilis, bacterial pharyngitis, Epstein-Barr virus, Stevens-Johnson syndrome, contact dermatitis, bullous impetigo, and enteroviruses.

The differential for genital ulcers includes syphilis, chancroid, drug eruptions, contact dermatitis, molluscum contagiosum, lymphogranuloma venerum, and Behcet’s disease.

D. Physical Examination Findings.

Primary HSV-1 generally presents with gingivostomatitis and pharyngitis. Patients can have tonsillar exudate, ulcerative lesions, cervical lymphadenopathy and constitutional symptoms such as fever, malaise, and myalgia.

Reactivation is usually in the form of herpes labialis (the classic “cold sore”).

Primary HSV-2 (genital) presents with painful genital ulcers, tender lymphadenopathy, and fever (Figure 1). Recurrent infection is less severe and the duration of lesions is shorter (10 vs 19 days).

HSV-1 encephalitis is a severe, life-threatening condition marked by altered mental status, fever, or seizures. If HSV encephalitis is suspected, treatment should begin immediately with IV acyclovir.

On the contrary, HSV-2 can cause self-limiting aseptic meningitis marked by headache, photophobia, neck stiffness. Recurrent aseptic meningitis caused by HSV-2 is termed, “Mollaret’s meningitis.”

E. What diagnostic tests should be performed?

The diagnostic test of choice is PCR.

The diagnosis is made clinically and rarely are the confirmatory laboratory tests needed. The Tzanck smear is still available but not performed by many and viral culture is very low yield. If serologic studies are positive, the diagnosis is generally assumed to be HSV.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

HSV PCR is becoming the gold standard in diagnosis, particularly with HSV encephalitis (discussed elsewhere).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Magnetic resonance imaging (MRI) brain should be obtained in patients with suspected HSV encephalitis. In most cases of HSV encephalitis, MRI will reveal edema and/or abnormal enhancement in one or both temporal and frontal lobes, the insular cortex, and the angular gyrus. If MRI cannot be obtained, computed tomography (CT) brain is acceptable, but less sensitive.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Viral culture again is very low yield.

III. Default Management.

Acyclovir, valacyclovir, and famciclovir can all be used to treat primary herpes and for suppression of recurrent infection and viral shedding. Therapy should be initiated within 72 hours of vesicular eruption, and ideally within 24 hours, as this decreases duration and severity of the outbreak. Suppressive therapy is recommended for patients with more than 4 genital herpes outbreaks a year. When used for suppressive therapy, studies have shown no difference in efficacy between the 3 antiviral medications.

Topical antivirals have a small and limited effect on the duration of recurrent oral lesions and do not require a prescription. These include docosanol, penciclovir, and acyclovir topical. However, most reviews found the benefit of topical antivirals to be marginal and of little clinical importance.

A. Immediate management.

Disseminated herpes simplex virus (mainly central nervous system, pulmonary, hepatic involvement)

Acyclovir 10 mg/kg IV every 8 hours for 10-21 days;
Intravenous fluids to reduce risk of acyclovir-induced crystal nephropathy;
Consult infectious disease specialist.

Primary oral herpes treatment

Acyclovir 200 mg by mouth (po) five times per day for 7-10 days; or 400 mg po three times a day (TID) for 7-10 days;
Valacyclovir 2000 mg po twice a day (BID) for 1 day;
Famciclovir 250 mg po TID for 7-10 days;
Symptomatic measures such as acetaminophen, ibuprofen, topical lidocaine.

Recurrent oral herpes treatment

Acyclovir 400 mg po TID for 5 days; or 800 mg po BID for 5 days; or 200 mg po 5 times a day for 5 days;
Valacyclovir 500 mg po BID for 3 days; or 1000 mg po daily for 5 days;
Famciclovir 1500 mg po once.

Suppressive oral herpes treatment

Acyclovir 400 mg po BID for 12 months;
Valacyclovir 500-1000 mg once daily for 12 months;
Famciclovir 250 mg po BID for 12 months.

Topical antivirals

Popular because they can be used without a prescription but not as effective as oral therapy.

Docosanol topical (Abreva^®) applied 5 times daily;
Penciclovir topical apply every 2 hours;
Acyclovir topical applied 5 times per day (Zovirax^®).

Primary genital herpes treatment

Acyclovir 400 mg po TID for 7-10 days; or 200 mg po five times per day for 7-10 days;
Valacyclovir 1000 mg po BID for 7-10 days;
Famciclovir 250 mg po TID for 7-10 days.

Recurrent genital herpes treatment

Acyclovir 800 mg po BID for 5 days; or 400 mg TID for 5 days or 800 mg po TID for 2 days;
Valacyclovir 500 mg po BID for 3 days; or 1000 mg once daily for 5 days;
Famciclovir 125 mg po BID for 5 days; or 1000 mg po BID for 1 day; or 500 mg as a single dose then 250mg BID for 2 days.

Suppressive genital herpes treatment

Acyclovir 400 mg po BID;
Valacyclovir 500 mg po daily; or 1000 mg po daily;
Famcyclovir 250 mg po BID.

If lesions persist despite appropriate antiviral medication, antiviral resistant HSV should be suspected. A viral isolate should be sent for sensitivity testing and infectious disease should be consulted. Foscarnet and cidofovir can be effective alternatives in cases with acyclovir resistant HSV.

B. Physical Examination Tips to Guide Management.

You will see the classic vesicular ulcerative lesions usually grouped with an erythematous base (Figure 2).

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There are no specific tests to monitor response to therapy. Treatment with antivirals generally decreases duration of symptoms. Recommend monitoring creatinine and blood urea nitrogen (BUN) as the antivirals should be renally dosed.

D. Long-term management.

Long-term management can be in the form of chronic suppressive therapy or episodic treatment.

E. Common Pitfalls and Side-Effects of Management

Antivirals can cause some renal impairment but are generally well tolerated. Common adverse effects include nausea, vomiting, diarrhea, and dizziness.

IV. Management with Co-Morbidities

Immunocompromised patients are at increased risk for disseminated and severe infection. Any concern for dissemination requires treatment with intravenous acyclovir. Foscarnet can be used as a second line agent in immunocompromised patients with oral or genital herpes.

A. Renal Insufficiency.

Antiviral therapy all needs to be dose adjusted in renal insufficiency.

B. Liver Insufficiency.

There is no adjustment of antivirals in hepatic insufficiency.

C. Systolic and Diastolic Heart Failure

Unless the patient has corresponding renal insufficiency, there is not dose adjustment in this condition.

G. Immunosuppression (HIV, chronic steroids, etc).

HIV patients are at increased risk for recurrent and more severe/disseminated HSV infections. These patients can present with extensive oral or perianal ulcers, meningoencephalitis, esophagitis, colitis, chorioretinitis, tracheobronchitis, pneumonia, and acute retinal necrosis. Genital HSV lesions can also increase sexual transmission of human immunodeficiency virus (HIV).

V. Transitions of Care

B. Anticipated Length of Stay.

Patients are generally not admitted to the hospital for management of HSV infections, unless it is disseminated or primary CNS involvement (encephalitis).

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Patients should follow-up with their primary care physician as needed after successful treatment of a herpes outbreak.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Tests conducted prior to discharge would include renal function and a complete blood count since antiviral therapy can lead to renal insufficiency, leukopenia, and thrombocytopenia.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

Generally, patients can be discharged to home.

F. Prognosis and Patient Counselling.

Counselling is a crucial aspect in the management of herpes. Patients should be counselled that herpes is a chronic, lifelong viral illness that may result in frequent recurrent outbreaks. Over time, patients learn their triggers, such as stress, as well as early prodromal symptoms to initiate immediate therapy. Patients should also be counselled on the appropriateness of chronic suppressive therapy versus episodic treatment for recurrences. Patients with genital herpes should inform their sexual partners of their genital herpes and use latex condoms to help reduce but not eliminate the risk of transmission. Lastly, patients need counselling on the risk of neonatal HSV transmission. Pregnant women should be asked if they have ever had genital herpes. Women with genital herpes lesions present at the time of labor should undergo caesarian delivery to reduce the risk of neonatal HSV.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

Patients with open VZV lesions should be placed on contact and airborne isolation.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Consideration for chronic suppressive therapy if a patient has severe frequent outbreaks.

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