Herpes Simplex Virus (HSV)/Varicella Zoster Virus (VZV)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has herpes simplex virus infection? What should you expect to find?

• Herpes simplex virus infection may be asymptomatic.

• For primary infections, symptoms occur approximately 3 days to 1 week after exposure to infection.

• Patients with primary infection may have a prodrome, which can include symptoms, such as fever, malaise, loss of appetite, and localized pain and/or burning at the site the lesions will occur.

• Prodrome may also occur in patients with recurrent lesions, but the symptoms are often decreased in severity and duration.

• Orolabial herpes (Figure 1): edema and pain may lead to dysphagia.

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• Genital herpes can be associated with extreme pain, edema, and dysuria. Systemic complaints are more common in women and may manifest with extragenital lesions, urinary retention, or aseptic meningitis. Recurrent lesions may have limited symptoms, and outbreaks occur on average from four to seven times per year.

• In immunosuppressed patients with human immunodeficiency virus (HIV), lesions occur more often, are more atypical, and are less likely to resolve on their own. Patients may experience severe pain and dysphagia leading to an inability to swallow oral medications and a need for hospitalization for intravenous medication.

• Skin lesions usually start as painful clustered vesicles on an erythematous base, which may progress to pustules and, ultimately, ulcerate.

• The ulcerations may cluster, forming one large ulcer with a scalloped border.

• Patients may have lymphadenopathy prior to or during a skin outbreak.

• Ulceration and crusting of lesions, with ultimate resolution, typically occurs in 2 to 6 weeks in immunocompetent patients; however, lesions may persist much longer in immunocompromised patients, such as those with HIV.

• For orolabial herpes (Figure 1), mouth (buccal and gingival mucosa) and lips are the most common sites. Recurrent lesions are commonly found on the vermilion border. Other sites may include perioral skin, nasal mucosa, and hard palate.

• Primary genital herpes can produce erosive balanitis, vulvitis, or vaginitis. In women, lesions can also involve the cervix, buttocks, and perineum. In men, lesions most often occur on the penile shaft or glans (Figure 2); recurrent lesions may occur on the genitals or buttocks and resolve within 1 week. Frequency of recurrent lesions may be related to the severity of the primary infection.

• In patients with HIV, lesions may lead to deep ulcerations around the nose, mouth, genitals, and even distal fingers (Figure 3, Figure 4, Figure 5). Verrucous or tumor-like lesions have been reported (Figure 6).

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Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

How did the patient develop herpes simplex virus infection? What was the primary source from which the infection spread?

• Herpes simplex virus (HSV) can be spread by infected individuals who are asymptomatic or symptomatic during times of viral shedding.

• HSV-1, which is more commonly associated with oral herpes, is primarily spread by contact with infected saliva or other secretions.

• HSV-2, which is more commonly associated with genital herpes, is primarily spread by sexual contact.

• The virus replicates at the site of infection, travels retrograde to the dorsal root ganglion, and establishes latent infection. Recurrent lesions occur with reactivation of latent disease.

• Triggers for reactivation of latent disease include stress, fever, immunocompromised state, damage to local tissue, and ultraviolet light.

Which individuals are of greater risk of developing herpes simplex virus infection?

• Oral disease is commonly acquired in childhood and 90% of young adults are HSV-1 antibody positive.

• Risk factors for acquiring genital disease are age 15 to 30 years, increased number of sexual partners, black or Hispanic race, and HIV positivity.

• As the cluster of differentiation (CD)4 count decreases in patients with HIV (particularly below 100 cells/mm³), prevalence of active herpes simplex virus infection increases.

Beware: there are other diseases that can mimic herpes simplex virus infection:

• Varicella zoster virus infection: Individual lesions of varicella zoster may look exactly like herpes simplex, with clustered vesicles or ulcers on an erythematous base. Varicella zoster tends to follow a dermatomal distribution, which can help to distinguish from herpes simplex. Disseminated herpes simplex and disseminated zoster may be indistinguishable clinically.

• Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): This may manifest with oral and/or genital ulcerations, which can mimic herpes simplex; however, there are often other clues to the diagnosis of SJS/TEN, such as concomitant ocular involvement, subepidermal blisters, full thickness epidermal sloughing, and involvement of the palms and soles.

• Aphthous ulcers: These occur most commonly in the mouth but can also involve the genitals, such as in Behcet disease. Large aphthous ulcers can be associated with HIV infection. These most commonly occur on the mucosal inner lips, tongue, floor of the mouth, and inner cheeks. They occur as small round ulcers with a yellow or grey ulcer floor, which often occur singly or in a linear fashion. They usually heal within 1 week.

• Additional mimickers of genital herpes:

  Syphilis: This is usually a single ulcer, which is painless, and usually not recurrent.

  Chancroid: These are painful ulcer(s) with a shaggy border and yellow/grey exudate.

  Lymphogranuloma venereum: This usually manifests as a painful papule that may ulcerate; can also be grouped herpetiform lesions initially; and may be associated with buboes, draining sinuses, and/or lymphedema.

  HIV infection: HIV may present with major aphthous ulcerations, which occur most commonly on the oral mucosa.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

• Serologic tests can show primary seroconversion for HSV-1 or HSV-2 infection; however, it does not definitively diagnose active disease.

Results that confirm the diagnosis

• Tzank smear: Scraping of the base of an early unroofed blister can demonstrate virally infected multinucleated epithelial giant cells.

• Tissue biopsy: Biopsy can show virally infected multinucleated epithelial giant cells.

• Viral tissue culture: This may be positive within 48 hours and can allow for resistance testing if needed.

• HSV deoxyribonucleic acid detection: Gene amplification by PCR, ligase chain reaction, or other methods can be done on skin lesions or cerebral spinal fluid (when evaluating for encephalitis and other infected tissue).

• Direct fluorescent antibody: Cells scraped from the base of an early unroofed blister are stained with a direct fluorescent antibody.

What imaging studies will be helpful in making or excluding the diagnosis of herpes simplex?

• Imaging studies are only useful when there is suspected HSV encephalitis. Brain imaging studies, such as computed tomography and magnetic resonance imaging scans, can be performed to look for involvement of the temporal lobe.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has herpes simplex virus infection, what therapies should you initiate immediately?

Dermatology would be most helpful in diagnosing this infection when there is skin or mucous membrane involvement.

If the patients are immunocompetent, no therapy may be necessary since the lesions usually self-resolve. If the patient is immunocompromised, severely symptomatic, or disseminated or the lesions are extensive, treatment is needed. Recommended medications for initial or recurrent infection include aciclovir, valaciclovir, and famciclovir (all evidence category A). Aciclovir resistant infection can be treated with intravenous foscarnet or topical cidofovir (evidence category C).

If the patient has frequent recurrences, chronic suppressive treatment may be an option.

1. Anti-infective agents (Table I)

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