Infectious Diseases

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.

  • 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).

Figure 1.

Cluster of vesicles on the lip, representing orolabial herpes.

Figure 2.

Genital Herpes Simplex: After the vesicles have ruptured, patients may manifest with an ulcer with a scalloped border.

Figure 3.

Extensive resistant herpes simplex virus infection on the face.

Figure 4.

Chronic peri-oral herpes around the mouth and nose.

Figure 5.

Chronic herpes ulcers in the genital area.

Figure 6.

Herpes simplex manifesting as a chronic verrucous follicular nodule.

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)

Table I.

Treatment Options for Herpes Simplex Virus Infection
Type of herpes simplex infection Antibiotic Dose Comments
Orolabial (recurrent) FamciclovirValaciclovir 1.5g orally for 1 dose2g orally twice a day for 1 day
Genital (primary) AciclovirFamciclovirValaciclovir 200mg orally 5 times a day for 10 days OR 400mg orally three times a day for 10 days250mg orally three times a day for 10 days1g orally twice a day for 10 days
Genital (recurrent) AciclovirFamciclovirValaciclovir 200mg orally 5 times a day for 5 days OR 400mg orally three times a day for 5 days1g orally twice a day for 1 day OR 125mg orally twice a day for 5 days500mg orally twice a day for 3–5 days
Chronic suppression AciclovirFamciclovirValaciclovir 400mgorally twice a day250mgorally twice a day500mg orally every day for <10 outbreaks/year OR 1g orally every day for 10 or more outbreaks per year
Genital (recurrent) in HIV patients AciclovirFamciclovirValaciclovir 200mg orally 5 times a day OR 400mg orally three times a day500mg orally twice a day1g orally twice a day Use until all lesions are healed
Chronic suppression in HIV patients AciclovirFamciclovirValaciclovir 400–800mg orally two to three times a day500mg orally twice a day500mg orally twice a day
Aciclovir resistance in HIV patients FoscarnetCidofovir 40mg/kg intravenously every 8–12 hours for 2–3 weeks (or until lesions healed)1% cream every day for 2–3 weeks Nephrotoxicity and electrolyte disturbances can occur with foscarnet.

What complications could arise as a consequence of herpes simplex virus infection?

What should you tell the family about the patient's prognosis?

Complications of severe oral herpes include dysphagia, severe pain, and inability to take oral medications. In HIV infection, oral or genital herpes can be persistent and cause deep painful ulcers. Bacterial and yeast superinfections can occur in patients with persistent ulcerations. Ocular infection can occur, particularly in association with oral herpes infection. Complications of genital herpes include dysuria, pain, and edema. Disseminated disease can lead to herpes encephalitis/meningitis, hepatitis/hepatic failure, disseminated intravascular coagulation, adrenal necrosis, interstitial pneumonitis, and esophagitis.

  • Risk factors for poor outcome include severe immunocompromised states, disseminated disease with visceral involvement, and resistant virus. Patients with advanced HIV infection are particularly at risk for poor outcome.

  • With the advent of highly active antiretroviral therapy, severe manifestations of herpes simplex in HIV are very uncommon.

How do you contract herpes simplex virus infection and how frequent is this disease?

Herpes simplex is distributed worldwide.

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.

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

Based on serology studies, the prevalence of HSV-2 in adults in the United States is between 40 and 60 million people. A levelling of prevalence is seen around age 30 suggesting that few new infections occur after that age.

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

As the CD4 count decreases in patients with HIV (particularly <100 cells/mm3), prevalence of active herpes simplex virus infection increases.

In two separate studies (Bauer et al., Johnson et al) age and race were the demographic factors most associated with HSV-2 prevalence.

In the first, the effect of age in increasing the odds of HSV-2 was modified by race, with higher HSV-2 prevalence among Black Americans established by 20 to 24 years of age and the effect of race decreasing from 30 to 49 years of age.

In the study by Johnson, the prevalence of the antibody increased from less than 1% in the group aged less than 15 years to 20.2% in the group aged 30 to 44 years; it increased only slightly thereafter. In the oldest group, aged 60 to 74 years, the prevalence was 19.7% in whites and 64.7% in blacks.

What pathogens are responsible for this disease?

The pathogens responsible for disease are HSV-1 and HSV-2.

How do these pathogens cause herpes simplex virus infection?

  • HSV can 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. The virus is able to avoid immune detection during latency, possibly through intracellular accumulation of CD1d molecules in antigen presenting cells. CD1d molecules are typically transported to the cell surface where they play a role in antigen presentation.

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

How can herpes simplex virus infection be prevented?

Chronic suppressive regimens of antiviral medications can be used to prevent outbreaks, reduce viral shedding, and decrease disease transmission. Barrier protection is useful for preventing transmission of genital herpes infection.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Bauer, GR, Khobzi, N, Coleman, TA.. "Herpes simplex virus type 2 seropositivity and relationship status among US adults age 20 to 49: a population-based analysis". BMC Infect Dis. vol. 10. 2010. pp. 359.

(Recent statistics on prevalence and risk factors for acquiring herpes-2 infection.)

Bartlett, BL, Tyring, S., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. "Herpes genitalis". Treatment of skin disease comprehensive therapeutic strategies. Saunders-Elsevier. 2010. pp. 340-42.

(This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A: double-blind studies, B: clinical trial with greater than or equal 20 subjects, C: clinical trial with less than 20 subjects, D: case series of more than four subjects, and E: anecdotal case reports.)

Khambaty, MM, Hsu, SS.. "Dermatology of the patient with HIV". Emerg Med Clin North Am. vol. 28. 2010. pp. 355-68.

(This is a great review of HIV-related dermatology, including many manifestations of infectious diseases, such as herpes simplex.)

Madkan, V, Sra, K, Brantley, J, Carrasco, D, Mendoza, N, Tyring, S., Bolognia, JL, Jorizzo, JL, Rapini, RP. "Human herpes viruses". Dermatology. Mosby-Elsevier. 2008. pp. 1199-217.

(This is an outstanding review of herpes simplex virus, including its relationship to patients immunocompromised by HIV infection.)

Martin, ET, Krantz, E, Gottlieb, SL. "A pooled analysis of the effect of condoms in preventing HSV-2 acquisition". Arch Intern Med. vol. 169. 2009. pp. 1233-40.

(The upshot is that condoms provide moderate protection of the order of 30%.)

Rodgers, S, Leslie, KS.. "Skin infections in HIV-infected individuals in the era of HAART". Curr Opin Infect Dis. vol. 24. 2011. pp. 124-9.

(This article emphasizes clinical findings, diagnosis, and treatment of skin infections in HIV-infected patients and how they have evolved in the era of HAART therapy.)

Wald, A, Corey, L, Timmler, B. "Helicase-primase inhibitor pritelivir for HSV-2 infection". N Engl J Med.. vol. 370. 2014 Jan 16. pp. 201-10.

(This industry sponsored placebo controlled study of 156 healthy individuals with HSV-2 showed a dose-dependent decrease in viral shedding and days with lesions with pritelivir.)

Johnston, C, Corey, L.. "Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding". Clin Microbiol Rev.. vol. 29. 2016 Jan. pp. 149-61.

DRG CODES and expected length of stay

  • 054: herpes simplex

  • 054.1: genital herpes

  • 054.10: genital herpes unspecified

  • 054.11: herpetic vulvovaginitis

  • 054.12: herpetic ulceration of the vulva

  • 054.13: herpetic infection of the penis

  • 054.19: other genital herpes infection

  • 054.2: herpetic gingivostomatitis

  • 054.3: herpetic meningoencephalitis

  • 054.4 herpes infection with ocular complication

  • 054.5: herpetic septicemia

  • 054.6: herpetic whitlow

  • 054.7: herpes simplex with other complications

  • 054.71: visceral herpes simplex

  • 054.72: herpes simplex meningitis

  • 054.73: herpes simplex otitis externa

  • 054.74: herpes simplex myelitis

For aciclovir resistant herpes, 2 to 3 weeks of intravenous antiviral medications are needed and the patients may be hospitalized during that time. Herpes encephalitis also requires 2 to 3 weeks of intravenous antiviral agents during hospitalization. Depending on the progression of disease, patients may require intensive care unit monitoring.

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