Varicella-Zoster Virus Infection

A 31-year-old previously healthy man had presented 1 week earlier to an outside emergency department (ED) with severe ear fullness, pain, and diminished hearing on the left side that had been present for several days. He was discharged and treated for otitis media with amoxicillin, but after 72 hours his symptoms worsened. Tender, vesicular erythematous lesions developed in his mouth and exclusively on the left side of his face, including his forehead, maxilla, and mandible (Figure).

He was brought to our ED by his fiancé, with a fever (temperature to 39.3°C [102.7°F]). His main complaint was severe frontal headache, which he described as sharp and squeezing, “like my head is in a vice,” with radiation across the top and back of his head bilaterally. The pain was exacerbated with any movement of his head and neck, especially with rapid movement, and was associated with anorexia, nausea/vomiting, and photophobia.

The patient and his fiancé have 2 children and have lived together for 5 years. The patient reported having had sex with up to an additional 100 female partners, whom he would solicit during “sex binges” during the couple’s frequent break-ups. He denied having sex with men. Condom use was sporadic. The patient denied any recent travel and exposure to chemicals. He has no pets or sick contacts. He works as a pharmacy technician but has not taken any new medications.

He denied visual disturbance, confusion, cough, sore throat, chest pain, abdominal pain, dysuria, focal weakness, tingling in the arms or legs, or genital lesions. This presentation is consistent with trigeminal zoster with meningitis secondary to varicella-zoster virus (VZV). The diagnosis was made clinically the day the patient was admitted, before results of confirmatory studies were available. The diagnosis was based on the appearance of vesicular lesions of the same age in the typical unilateral trigeminal distribution. A direct fluorescent antibody test was performed on the forehead skin lesion, which was positive for VZV.

Although many of us were taught to look for the appearance of VZV on a single branch of the trigeminal nerve, the truth is that all 3 branches of the trigeminal nerve stem from a single dorsal nerve root ganglion. Together they constitute a single dermatome.

The dorsal root ganglion exists along the border of the dura mater. Thus, inflammation of the dorsal root can cause a subclinical meningeal irritation. In this case, however, true meningitis was suspected based on the clinical presentation, and lumbar puncture was performed. CSF was sent for various studies including a polymerase chain reaction (PCR) assay, results of which were positive for VZV.

CASE DISCUSSION
Acute varicella virus infection presents in childhood as a highly contagious cutaneous infection (commonly called “chickenpox,” with acute pustular lesions in various stages of development, fever and malaise. VZV reactivation, also known as shingles, results from reactivation of endogenous latent VZV infection within the sensory ganglia. This clinical form of the disease is characterized by a painful, unilateral vesicular eruption, which usually occurs in a restricted dermatomal distribution. Approximately 75% of cases are associated with acute neuritis, which precedes the appearance of skin lesions.

Clinically evident viral meningitis develops in a small subset of immunocompetent patients with herpes zoster (an estimated 0.5% of infected patients).¹ In these cases, lumbar puncture typically demonstrates a brisk CSF pleocytosis and an elevated protein concentration.^2,3 CSF studies confirm the presence of the virus.

VZV DIAGNOSTIC TESTING
Confirmatory diagnostic studies can include direct fluorescent antibody, PCR, and/or culture medium growth. PCR has a 95% to 100% sensitivity when the sample is collected properly. Per the CDC, vesicles should be unroofed in a sterile manner, and the base of the vesicle rubbed vigorously with a sythnetic swab with a plastic stem, pressing the base of the vesicle to express more fluid and epithelial cells laden with viral particles. Specimens should be transported in sterile tubes, and kept dry-without any transport media. Several studies conducted in patients with herpes zoster have demonstrated that subclinical meningeal irritation, evidenced by a reactive CSF pleocytosis, can occur in 40% to 50% of cases.⁴ Diagnosis of meningitis is initially made clinically by the appearance and distribution of the rash with severe headache and meningeal signs. This patient had confirmed VZV meningitis; PCR of CSF clearly demonstrated the presence of virus.

The overall goals of antiviral therapy are to promote more rapid healing of skin lesions, to lessen the severity and duration of pain associated with acute neuritis, and to reduce the incidence or severity of postherpetic neuralgia.*

VZV TREATMENT
Antiviral therapy is recommended for patients older than 50 years with uncomplicated herpes zoster who present within 72 hours of clinical symptoms (grade 1A ). The benefit of antiviral therapy in younger patients is not as clear, although the risk of adverse events is low.

We suggest antiviral therapy for patients younger than 50 with herpes zoster who present within 72 hours of clinical symptoms (grade 2C). Consider intravenous acyclovir for patients with more severe infections (ie, disseminated disease, meningitis, or ophthalmic involvement.

All HIV-infected patients should be treated with antiviral therapy for episodes of uncomplicated varicella zoster, regardless of the patient’s age at onset.

Once the decision to treat herpes zoster is made, select the treatment regimen based on the area affected that requires the highest or most invasive dosing regimen. Most trials have demonstrated that early antiviral treatment for herpes zoster reduces the duration or incidence of postherpetic neuralgia.* Glucocorticoids are not generally recommended; they do not decrease postherpetic neuralgia risk, as was once thought (grade 1B).* Analgesics are often needed at presentation to address symptoms of acute neuritis.

VZV Vaccine
The VZV vaccine is thought to reduce the occurrence of VZV reactivation, and more dramatically reduces the development of post-herpetic neuralgia.

THIS PATIENT’S CLINICAL COURSE
This patient’s initial presentation, with ear pain, fullness, and diminished hearing, was initially misdiagnosed as an ear infection. Diagnosis of VZV infection was likely missed because the primary lesion appeared within the ear canal (herpes zoster oticus, occurring in 0.2% of patients), which was more difficult to visualize.

Subsequent diagnosis was only made by maintaining a high clinical suspicion for VZV, because the facial lesion presentation was less typical of VZV; the pain was focal, moderate, and did not appear before lesion outbreak, but appeared in concert with each lesion itself. Also the lesions were distributed among all 3 branches of the trigeminal nerve.

In this case, treatment was started based on the initial clinical presentation and diagnosis with VZV. Intravenous therapy was selected based on multiple clinical factors in this case, any of which would independently warrant IV therapy. The clinical factors in this case included:

•    The presence of disseminated zoster (skin plus CSF)
•    The presence of herpes zoster meningitis
•    The continued development of new lesions
•    The presence of lesions involving the trigeminal nerve branch I and II, which is concerning for serious ocular and otic lesions
•    The confirmed presence of lesions on the eye and ear
•     The initially suspected immunocompromised (HIV) status based on sexual exposure

In this case, the frontal branch within the first division of the trigeminal nerve was involved, which puts the patient at risk for herpes zoster ophthalmicus (HZO)-a sight-threatening condition linked to VZV reactivation within the trigeminal ganglion. Incidence rates of HZO complicating herpes zoster in various population surveys range from 8% to 56%. The frontal branch within the first division of the trigeminal nerve is most frequently involved; 50% to 72% of patients experience direct ocular involvement. Ocular complications include uveitis and keratitis.

HIV infection was initially presumed in this case, based on the patient’s sexual history and presence of disseminated zoster, an AIDS-defining illness. Screening tests for HIV infection were negative. Testing for HIV RNA viral load and CD4 count was subsequently performed, in case results of the HIV rapid screening test were not yet positive. There was no evidence of HIV infection.

This patient was treated with acyclovir, 10 mg/kg/dose, every 8 hours for 21 days. An immediate improvement in lesions was noted. At 7 days, lesions appeared to be well healed. 

Dermatology was consulted the day after admission and performed a direct fluorescent antibody test of the forehead skin lesion.

TEACHING POINTS:
1. A young patient who presents with VZV infection should be evaluated for HIV.
2. A patient who presents with facial zoster with headache should undergo lumbar puncture to evaluate for the presence of VZV meningitis, since results will change management. In this patient’s case, the PCR showed VZV in the CSF. IV acyclovir was used rather than an oral equivalent.
3. Facial zoster should receive prompt and careful evaluation, especially if the patient complains of eye symptoms. A prompt referral to the ophthalmologist should be made if eye involvement is suspected based on symptoms or physical exam.
4. Any patient with dermatomal VZV should be placed on contact precautions. Strict contact plus airborne precautions should be instituted if disseminated VZV is suspected (defined as 20 or more lesions, more than 2 dermatomes, or skin and CSF involvement), if the patient is immunocompromised or suspected to be.
5. In adults, zoster is a treatable condition. Acyclovir is first-line treatment. It can hasten the recovery of active lesions and help prevent post-herpetic neuralgia.
6. Anyone over age 50 should receive the zostavax vaccine,* which helps prevent reactivation of hibernating varicella virus into the zoster form, and decreases the incidence of post-herpetic neuralgia.

*VZV vaccination guidelines have recently changed. It is not recommended that all people over 50-not the previously recommended age 60-should receive the VZV vaccine, as long as the patient is not immunocompromised and has no other contraindications.

References
1. Kupila L, Vuorinen T, Vainionp R, et al. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology. 2006;66:75.
2. Echevarra JM, Martnez-Martn P, Tllez A, et al. Aseptic meningitis due to varicella-zoster virus: serum antibody levels and local synthesis of specific IgG, IgM, and IgA. J Infect Dis. 1987;155:959.
3. Kudesia G, McKendrick MW. Clinical features of viral meningitis in adults: significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections. Clin Infect Dis. 2008;47:783.
4. Gold E. Serologic and virus-isolation studies of patients with varicella or herpes-zoster infection. N Engl J Med. 1966;274:181.