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CASE 4

The patient was a 20-year-old female who presented to the emergency room with a 4-day history of fever, chills, and myalgia. Two days prior to this she had noted painful genital lesions. On the day of admission she developed headache, photophobia, and a stiff neck. Previously she had been in good health. She admitted to being sexually active but had no history of sexually transmitted infections.

On physical examination, she was alert and oriented. Her vital signs were normal except for a temperature of 38.5°C (101.3°F); pulse rate was 80 beats/min, and blood pressure was 130/80 mm Hg. A general examination was unremarkable except for slight nuchal rigidity. Her throat was clear, and there was no lymphadenopathy. A pelvic examination revealed extensive vesicular and ulcerative lesions on the left labia minora and majora with marked edema. The cervix had exophytic (outward-growing) necrotic ulcerations.

General laboratory tests were unremarkable. A vaginal swab was collected for Neisseria gonorrhoeae and Chlamydia trachomatis nucleic acid amplification test (NAAT), a swab of the lesions was sent for herpes simplex virus (HSV) NAAT, and an RPR (rapid plasma reagin) was performed. A lumbar puncture was also done, which had a normal opening pressure. The cerebrospinal fluid (CSF) showed a mild pleocytosis with a leukocyte count of 41/μl with 21% polymorphonuclear leukocytes and 79% mononuclear cells, a glucose level of 46 mg/dl, and a protein level of 68 mg/dl (slightly elevated). The RPR and a CSF VDRL test were negative. A NAAT was positive from the lesion as well as from her CSF. The patient’s condition improved after 2 days of intravenous therapy. She was discharged home on oral medication.

1 1. What is the differential diagnosis of ulcerative genital lesions? Which rapid test was used so that specific therapy could be started?

2 2. Which complication of her underlying illness did she develop?

3 3. If she had been pregnant at the time of her infection, for what would her fetus be at risk?

4 4. Briefly describe the natural history of this infection.

5 5. Briefly describe the epidemiology of the agent causing her infection.

6 6. There are two different serotypes of the agent causing her infection. What similarities do they share and what are the differences between these agents?

CASE 4 CASE DISCUSSION

1. In the United States, the most likely diagnosis is either genital herpes or syphilis. In studies of patients with genital lesions in the industrialized world, HSV is the most frequently recovered agent. Other agents that are common causes of genital lesions include Haemophilus ducreyi (the etiologic agent of chancroid), human papillomavirus (genital warts), and the lymphogranuloma venereum-causing serotypes of C. trachomatis. Genital herpes lesions are painful, whereas lesions due to Treponema pallidum are usually painless. Genital infections such as chancroid or lymphogranuloma venereum can result in painful or painless ulcers, respectively, but they often result in suppurative lymphadenopathy. The diagnosis of HSV infection can be confirmed by swabbing the base of the lesion and performing either viral culture or NAAT. Using a shell vial culture technique, the virus can usually be detected within 24 hours. However, detection of HSV antigen by immunofluorescence or DNA from the lesion by NAAT is more rapid than culture. In addition, NAAT testing of lesions may be more sensitive than culture, though it is critical to monitor for laboratory contamination since these specimens contain high viral titers. To date, there is only one FDA-cleared NAAT for HSV, which is only approved for vaginal lesion swabs. Tzanck preparations, in which smears taken from the edge of the lesion are examined for the presence of cells showing pathologic changes consistent with HSV infection, can also be used in the diagnosis of genital lesions. This technique, although inexpensive, lacks both the sensitivity and specificity of culture, immunofluorescence, or NAAT. HSV was detected in this patient by an HSV NAAT performed on a swab of her genital lesion, which was positive for HSV-2.

2. Among women with primary genital herpes due to HSV-2, approximately one in three will have self-limited, aseptic meningitis. These patients typically have a pleocytosis with a lymphocytic predominance and an elevated protein level, as was seen in this case. In this clinical setting, CSF would not always be obtained. A NAAT was positive from the lesion as well as from her CSF. While HSV NAAT testing on lesions performs similarly to culture, NAAT testing on CSF is much more sensitive than culture. When CSF cultures were standard laboratory practice, the rate of isolation of HSV-2 was 0.5 to 3.0% in patients with aseptic meningitis. Now that NAAT testing of CSF is the reference method, the rate of detection of HSV-2 has increased to 5 to 17%.

3. Her fetus would be at risk for neonatal herpes. Neonatal herpes is a relatively infrequent infection, occurring in between 1 in 1,700 and 1 in 12,500 births. However, it is estimated that 25 to 50% of women who have acquired HSV during pregnancy and have vaginal deliveries will transmit the disease to their child, whereas ≤1% with recurrent infection will do so. Notably, most cases of genital HSV in women are asymptomatic, though cervical viral shedding still occurs. Other factors that increase the likelihood of infection are prolonged rupture of membranes, a mother who is seronegative for HSV-2 (suggesting acute infection), and the use of fetal scalp monitors. Of neonates with herpes infections, ~80% are infected during passage through an infected birth canal, while ~6 to 14% are infected in utero and the remaining are infected postpartum.

Most neonatal HSV infections occur in the second to third week of life. There are three forms of neonatal HSV infection: (i) skin, eyes, and mouth disease; (ii) central nervous system (CNS) disease; and (iii) disseminated disease. The most benign form, which is seen in 45% of cases, causes infection localized to the skin, eyes, and mouth. If recognized, it can be effectively treated with antiviral agents such as acyclovir. CNS-associated infections account for 30% of cases. These children have nonspecific CNS symptoms not unlike those of neonatal bacterial meningitis, including seizures, lethargy, high fevers, poor feeding, and irritation. Lesions may or may not be present. Mortality approaches 50% in untreated children, and long-term neurologic sequelae such as developmental delay, epilepsy, blindness, and cognitive disabilities are seen in half of the survivors. The most severe manifestation of disease is disseminated infection, which occurs in ~25% of cases. In this infection, multiple organs, including the brain, may be infected. These individuals typically have a viral exanthem in the setting of CNS infection and/or multiorgan failure. Up to 50% of cases do not have a rash. If the infection is untreated, mortality is very high, reaching 80%. Even with appropriate therapy, mortality for disseminated disease is 30%, and those who survive often have profound neurologic sequelae as mentioned above.

4. HSV, like all herpesviruses, causes a lifelong, latent infection. In genital tract infections, the virus enters a latent state in the sacral nerve ganglia. Recurrences occur when the virus replicates in the neuron and is carried along the peripheral nerves to the epithelium. Of adults with HSV-2, only 10 to 25% have a clinical history of genital herpes lesions. HSV-infected individuals can intermittently shed HSV in the absence of symptoms and therefore contribute to the transmission of HSV. Both condom use and antiviral suppression decrease transmission. Symptomatic recurrences may occur as frequently as 8 to 10 times per year, although the majority of individuals have significantly fewer episodes. Recurrences are generally milder than the primary episode of disease.

5. HSV-2 infects ~16% of individuals in the United States. Infections are more common in females (21%) than in males (12%) and are more common in black individuals (39%, versus 12% for whites). Other risk factors for HSV-2 infection include early age of first sexual encounter, a high number of sexual partners, history of other sexually transmitted infections, and lower socioeconomic status. Infection rates among commercial sex workers may approach 100%. Although HSV-2 infection rates increased significantly from 1976 to 1994, with the highest rate of increase in individuals <30 years old, this trend has reversed in recent years.

6. There are two distinct serotypes of HSV—HSV-1 and HSV-2. HSV-1 is an infection primarily of the oropharyngeal mucosa, with latent infection occurring in the trigeminal ganglion, while HSV-2 primarily infects the genital mucosa, though either serotype can be seen in these anatomic sites. HSV-1 infections are typically acquired in early childhood, while HSV-2 infections occur after the individual becomes sexually active. There has been a noticeable increase in HSV-1 genital infections over the last 2 decades, with some studies quoting an incidence of up to 50%. Possible explanations for this increase include increased oral-genital contact; increased HSV-1 acquisition in childhood, providing more viral exposure in adolescence; and/or a decrease in HSV-1 infection in childhood, making children more susceptible when they become sexually active. Although both serotypes are neurotropic, HSV-1 appears to cause more severe CNS infection affecting the temporal and frontal lobes. In contrast to aseptic meningitis associated with primary genital HSV-2 infection and neonatal CNS infection, herpes encephalitis in adults and older children is most often due to HSV-1 infection. Herpes encephalitis is a rare, sporadic CNS viral infection and is the most common cause of nonepidemic viral encephalitis in adults in the United States. Patients present with fever, headache, and encephalopathic findings such as altered consciousness, behavioral and speech disturbances, and focal or diffuse neurologic signs. The diagnosis can be confirmed by detecting HSV directly using fluorescent antibody staining of tissue obtained by brain biopsy. Because brain biopsy is dangerous, alternative means of making this diagnosis have been sought. Two studies have carefully evaluated the sensitivity of HSV PCR compared with histopathologic evaluation of brain tissue, reporting sensitivities of 97 to 98% for PCR. Therefore, HSV PCR of CSF has become the standard method for diagnosing HSV CNS infection. It is not clear why certain patterns of CNS infection with either HSV-1 or HSV-2 result in different CNS manifestations. The age of the patient, the route of viral dissemination (e.g., neural versus hematogenous), preexisting immunity, and/or specific viral properties may be factors.

REFERENCES

1. Centers for Disease Control and Prevention (CDC). 2010. Seroprevalence of herpes simplex virus type 2 among persons ages 14-49 years—United States, 2005–2008. MMWR Morb Mortal Wkly Rep 59:456–459.

2. Corey L, Wald A. 2009. Maternal and neonatal herpes simplex virus infections. N Engl J Med 361:1376–1385.

3. Lakeman FD, Whitley RJ, National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. 1995. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. J Infect Dis 171:857–863.

4. Tang YW, Mitchell PS, Espy MJ, Smith TF, Persing DH. 1999. Molecular diagnosis of herpes simplex virus infections in the central nervous system. J Clin Microbiol 37:2127–2136.

5. Whitley RJ, Roizman B. 2001. Herpes simplex virus infections. Lancet 357:1513–1518.