Herpes Simplex Viruses Case File

Herpes Simplex Viruses Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 28

The mother of a 3-year-old girl brings the child in for the evaluation of a “wart” on her thumb. It has been present for 3 or 4 days and seems to cause some pain. The week prior, the child had a “head cold” and “cold sores” around her mouth, all of which have resolved. She has never had warts, and the mother says that the child is otherwise healthy. On examination, you see a well appearing child who is sitting in her mother’s lap and sucking her thumb. Her head and neck exam is normal. On her left thumb, just proximal to the base of the thumbnail, is the lesion about which the mother is concerned. It is a cluster of small vesicles with a faint area of surrounding erythema. The remainder of the child’s examination is normal.

◆ What virus is the most likely cause of this skin lesion?

◆ How was it transmitted to this patient’s thumb?

ANSWERS TO CASE 28: HERPES SIMPLEX VIRUSES

Summary: A 3-year-old girl had “cold sores” previously and now a cluster of small vesicles with a faint area of surrounding erythema on the thumb, consistent with herpetic whitlow.

◆ Most likely viral cause of this skin lesion: The most likely cause of the girl’s skin lesion is herpes simplex type 1 (HSV-1).

◆ How was it transmitted to this patient’s thumb: The patient most likely acquired the infection at this secondary site via self-inoculation of the skin by sucking her thumb.

CLINICAL CORRELATION

There are two serotypes of herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), which both cause vesicular lesions via infection of mucosal membranes and or compromised epithelial cells. Both HSV-1 and HSV-2 are known to replicate in the basal epithelium of these vesicular lesions and then establish latent and recurring infections within the innervating neurons of these cells. HSV primarily cause clinical symptoms at the site of inoculation of the virus. Although there is some overlap, HSV-1 tends to cause disease above the waist, and HSV-2, which is more commonly transmitted via sexual contact, causes disease below the waist.

APPROACH TO SUSPECTED HSV INFECTION

Objectives

1. Know the structure and characteristics of HSV.
2. Know the clinical disease caused by HSV, mode of transmission, and strategies for treatment.

Definitions

Vesicular lesions: Small, blister-like lesions filled with clear fluid.

Syncytia: Fusion of neighboring cells infected with virus, resulting in multinucleated giant cells.

Gingivostomatitis: Localized inflammation and or ulcerative lesions in the mucous membranes of the oral cavity.

Prodrome: Early symptoms of HSV infection, including itching and tingling of skin 12–24 hours prior to lesion formation.

DISCUSSION

Characteristics of HSV That Impact Transmission

The herpes simplex viruses (HSV) are members of the Alphavirinae subfamily of human herpesviruses. As with other herpesviruses, they are large, enveloped viruses containing linear, double-stranded DNA genomes surrounded by an icosadeltahedral nucleocapsid, with a protein tegument (space containing viral enzymes and transcription factors) located between the capsid and viral envelope. The structures of the HSV-1 and HSV-2 genomes are similar and share approximately 50 percent homology. They can infect many cell types in humans and in other animals. They tend to cause lytic infections in fibroblast and epithelial cells and latent infections in neurons. HSV enters host cells via fusion at the cell membrane and releases gene transcription proteins, protein kinases, and proteins that are cytotoxic to the host cell. Once inside the host, the viral genome is delivered to the nucleus of the cell. HSV uses the host transcription/translation machinery; yet it is a viral-encoded DNA polymerase that replicates the DNA genome. Newly formed enveloped virions are released from the cell by either exocytosis or cell lysis.

The virus enters through mucosal membranes or breaks in the skin. It replicates in cells at the infection site and then establishes latent infection of the neuron that innervates the primarily infection site via retrograde transport. HSV avoids antibody-mediated defenses by cell-to-cell spread by the formation of syncytia. Cell-mediated immunity is necessary for control of HSV infections, and persons with impaired cellular immunity can get more severe and diffuse disease. The latent infection of neurons also helps the virus to avoid host defenses and provides the potential for recurrent disease. Recurrences can be triggered by many events, including stress and other illnesses. Recurrent HSV disease is usually less severe than primary disease because of the memory response of the host immune system. HSV-1 tends to be transmitted via contact with saliva or direct contact with skin or mucous membrane lesions. It causes gingivostomatitis, cold sores, and pharyngitis. Herpetic whitlow, an infection of the finger with HSV-1, results from direct contact with herpes lesions and is most commonly seen in children who suck their fingers or in health-care workers who care for infected patients.

Diagnosis

Clinical signs of HSV-1 and HSV-2 infections include (1) oropharyngeal disease, with symptoms of fever, sore throat, gingivostomatitis, and submandibular lymphadenopathy; (2) keratoconjunctivitis, with recurrent lesions of the eye and eyelid; (3) cutaneous infections, with vesicular lesions of the mouth, fingers, and genital tract (Figure 28-1); and (4) encephalitis. Neonatal infections occur most commonly during vaginal delivery in pregnant mothers experiencing primary or recurrent genital lesions. HSV neonatal infections are nearly always symptomatic and have high mortality rates if not promptly diagnosed and treated. Signs of infection include localized vesicular lesions of the skin, eye or mouth, encephalitis, and/or disseminated disease.

Figure 28-1. First episode primary genital herpes simplex virus infection. (Reproduced, with permission, from Cunningham FG, et al. William’s Obstetrics, 21st ed. New York: McGraw-Hill, 2001:1495.)

Cytopathologically, HSV can be diagnosed by visualizing multinucleated giant cells on direct examination of cells from the base of a vesicular lesion, referred to as a Tzanck smear. However, this assay lacks both sensitivity and specificity, because it does not distinguish among HSV-1, HSV-2, and varicella-zoster virus (VZV) infections. Isolation of virus from herpetic lesions, cerebral spinal fluid, or stool specimens remains the definitive diagnostic approach, where the appearance of characteristic HSV cytopathic effects on cells can be observed. Other rapid diagnostic tests include: detecting viral antigen (via immunofluorescence) or DNA (via PCR) in tissue samples or vesicle fluid. HSV-1 and HSV-2 serotyping can be performed by several biochemical, nucleic acid, or immunologic methods, with DNA probe analysis being the most widely used in current clinical practice.

Treatment and Prevention

Several antiviral drugs have been developed to treat HSV infections, including acyclovir, valacyclovir, and famciclovir. All of these drugs function as inhibitors of viral DNA synthesis and are capable of shortening the duration of clinical symptoms and suppressing viral reactivation.

Prevention of HSV infection relies on the avoidance of direct contact with the virus or viral lesions. Asymptomatic shedding of virus can occur in infected persons in saliva, urethral, and cervical sources, and because only about onefourth of individuals infected with HSV know that they are infected, safe sex practices are highly recommended to avoid spread. The vast majority of HSV infections in newborns can be prevented by cesarean delivery of neonates in women experiencing primary HSV-2 infection or recurrent genital lesions. This practice has significantly decreased the rate of neonatal infection and mortality. Additionally, experimental recombinant HSV-2 vaccines are currently being developed and tested. One prospective trial has shown efficacy in preventing genital herpes infections in HSV-1 and HSV-2 seronegative women.

COMPREHENSION QUESTIONS

[28.1] Which of the following cell types are specific to a latent genital infection with HSV-2?

A. Trigeminal ganglia

B. Sacral ganglia

C. Vagal nerve ganglia

D. Neural sensory ganglia

[28.2] Which of the following viruses, in addition to HSV-1 and HSV-2, produces the cytopathologic findings of multinucleated giant cells?

A. Adenovirus

B. Cytomegalovirus

C. Epstein-Barr virus

D. Human papillomavirus

E. Varicella-zoster virus

[28.3] Which of the following statements most accurately describes HSV infections?

A. HSV establishes lytic infection in neural ganglion cells.

B. Latent HSV infections can be prevented in persons with functional cell-mediated immunity.

C. Primary and recurrent HSV infections are treated with drugs that inhibit the viral DNA polymerase.

D. HSV infection is transmitted via direct contact with symptomatic shedding of viral particles in active lesions.

E. Severe neonatal herpes infections are commonly associated with in utero transmission.

Answers

[28.1] B. Latent infection by HSV-2 has been shown to occur primarily in the sacral ganglia, whereas HSV-1 latency has been demonstrated in trigeminal, superior cervical, and vagal nerve ganglia. Varicellazoster virus remains latent in neural sensory ganglia.

[28.2] E. A Tzanck smear assay can be used to identify the characteristic cytopathologic effects of multinucleated giant cells in herpetic skin lesions; however, this assay cannot distinguish among HSV-1, HSV-2, and VZV infections.

[28.3] C. Most antiviral therapies for HSV are nucleoside analogues or other inhibitors of the viral DNA polymerase; answers A, B, D, and E are incorrect: HSV establishes lytic infections in fibroblast and epithelial cells and latent infections in neurons; infection with HSV results in lifelong latent infection even in persons with functional cell-mediated immunity; HSV is transmitted most commonly from direct contact with active lesions (however, virus may be shed asymptomatically in saliva and urethral and cervical fluids); although in utero transmission of HSV is possible, it is very uncommon, and most neonatal HSV infections occur via vaginal delivery in mothers with primary genital infections.

MICROBIOLOGY PEARLS ❖ Clinical manifestations include painful vesicular lesions of the mouth, fingers, and genital tract. ❖ Characteristic viral cytopathology includes syncytia, cells with “ballooning” cytoplasm, and Cowdry A type inclusion bodies. ❖ Diagnosis of infection is made by viral isolation; HSV-1 and HSV-2 serotyping is performed by nucleic acid restriction mapping or DNA probe analysis. ❖ Effective treatment of primary and recurrent infections is with viral DNA polymerase inhibitors: acyclovir, valacyclovir, and famciclovir.

REFERENCES

Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology, 5th ed. St. Louis, MO: Mosby, 2005:543–50. 

Ryan JR, Ray CG. Sherris Medical Microbiology, 4th ed. New York: McGraw-Hill, 2004:555–62. 

Whitley, RJ, Kimberlin, DW, Roizman, B. Herpes simplex viruses. J Clin Infect Dis 1998;26:541–55.

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