Varicella-Zoster Virus

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Practice Essentials

Varicella-zoster virus (VZV) causes chickenpox and herpes zoster (shingles). Chickenpox follows initial exposure to the virus and is typically a relatively mild, self-limited childhood illness with a characteristic exanthem, but can become disseminated in immunocompromised children. Reactivation of the dormant virus results in the characteristic painful dermatomal rash of herpes zoster, which is often followed by pain in the distribution of the rash (postherpetic neuralgia). See the image below.



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Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.

Signs and symptoms

Pain and paresthesia are typically the first symptoms of VZV infection. Until the characteristic vesicular rash erupts, diagnosis may be difficult. A prodromal period during which symptoms may vary is common. Pain occurs in 41% of patients, itching in 27%, and paresthesias in 12%.

During the acute illness, patients may experience the following:

Herpes zoster (shingles)

Zoster multiplex

Zoster sine herpete

VZV infection may reactivate without causing cutaneous vesicles. These patients have severe dermatomal pain, possible motor weakness and possible hypesthesia, but no visible rash or vesicles.

VZV infection may present as acute peripheral facial palsy in 8-25% of patients who have no cutaneous vesicles. This is more common in immunosuppressed patients who use acyclovir (or other agents) as zoster prophylaxis.[1]

Central nervous system deficits

Ramsay-Hunt syndrome

This syndrome occurs when the geniculate ganglion is involved. The clinical presentation includes the following:

Keratitis (herpes ophthalmicus)

See Clinical Presentation for more detail.

Diagnosis

When the presentation includes the typical dermatomal rash, additional studies are not required. Studies to consider in specific situations include the following:

See Workup for more detail.

Management

Treatment options are based on the following:

Antiviral medications decrease the duration of symptoms and the likelihood of postherpetic neuralgia, especially when initiated within 2 days of the onset of rash. Oral acyclovir may be prescribed in otherwise healthy patients who have typical cases. Compared with oral acyclovir, other medications (eg, valacyclovir, penciclovir, famciclovir) may decrease the duration of the patient's pain.

Varicella zoster immune globulin (VariZIG) is indicated for administration to high-risk individuals within 10 days (ideally within 4 days) of chickenpox (VZV) exposure.[2] High- risk groups include the following:

See Treatment and Medication for more detail.

Background

Varicella-zoster virus (VZV) is the cause of chickenpox and herpes zoster (also called shingles). Chickenpox follows initial exposure to the virus and is typically a relatively mild, self-limited childhood illness with a characteristic exanthem.

Approximately 1 per 4000 children develops VZV encephalitis, an acute neurologic disorder with potentially severe complications. In addition, immunocompromised children (eg, those receiving chemotherapy for leukemia or those with advanced HIV infection) can develop disseminated VZV infection, a potentially fatal complication.

After primary infection, VZV remains dormant in sensory nerve roots for life. Upon reactivation, the virus migrates down the sensory nerve to the skin, causing the characteristic painful dermatomal rash. After resolution, many individuals continue to experience pain in the distribution of the rash (postherpetic neuralgia). In addition, reactivation of VZV infection can cause a spectrum of atypical presentations, ranging from self-limited radicular pain without rash to spinal cord disease with weakness.

Pathophysiology

The host immunologic mechanisms suppress replication of the virus. Reactivation can occur if host immune mechanisms are compromised. This may be caused by medications, illness, malnutrition, or by the natural decline in immune function with aging. Upon reactivation, the virus migrates along sensory nerves and produces sensory loss, pain, and other neurologic complications. If motor nerve roots are also involved, weakness can develop in addition to sensory changes. Leptomeningeal involvement is rare but may develop when the ophthalmic branch of the trigeminal nerve is involved.

Frequency

United States

The rate of occurrence is about 5 persons per 1000 population. Immunosuppression increases this risk. The risk of postherpetic neuralgia increases with age. Approximately 50% of patients older than 60 years may have temporary or prolonged pain syndrome.

The frequency of VZV infection may decrease as the immunized children become adults.

International

VZV infection occurs with the same frequency in the United States and internationally.

Mortality/Morbidity

Severe pain and insomnia are most bothersome to patients. About 95% of patients with zoster experience severe pain during the illness.

Other presentations of zoster, including ocular (keratitis) and spinal cord (myelitis) presentations, may result in additional morbidity.

Bacterial superinfection (impetiginization) of vesicular skin lesions can occur.

Race

The vesicular eruption of VZV infection may be more difficult to diagnose in patients with darker skin.

Sex

VZV infection occurs with equal frequency in males and females.

Age

After primary infection, zoster can occur at any age. However, the risk of zoster increases with age.

The risk of postherpetic neuralgia also increases with advancing age.

History

Pain and paresthesia are typically the first symptoms. Until the characteristic vesicular rash erupts, diagnosis may be difficult.

A prodromal period during which symptoms may vary is common. Pain occurs in 41% of patients, itching in 27%, and paresthesias in 12%.

During the acute illness, 90% of patients experience pain, 20% describe helplessness and depression, and 12% experience flulike symptoms.

Physical

Herpes zoster (shingles)

The most common presentation is the shingles vesicular rash, which most commonly affects a thoracic dermatome.

After a prodromal illness of pain and paresthesias, erythematous macules and papules develop and progress to vesicles within 24 hours. The vesicles eventually crust and resolve.

Pain and sensory loss are the usual symptoms, but motor weakness also occurs and is frequently missed on examination. Motor weakness results when the viral activity extends beyond the sensory root to involve the motor root. Cases of actual monoplegia due to varicella-zoster virus (VZV) brachial plexus neuritis have been reported.



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Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.



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Human herpesvirus (HHV) type 3. Intraoral herpes zoster closely resembles recurrent HHV-1 infection, but the lesions generally follow a dermatome and ....

Zoster multiplex

Shingles may appear in multiple dermatomes, both contiguous and noncontiguous, on either side of the body.

They are more common in individuals who are immunocompromised.

Terminology depends on the number of involved dermatomes and on whether the condition is unilateral or bilateral. For example, zoster duplex unilateralis refers to the involvement of 2 unilateral dermatomes. Cases of zoster simultaneously occurring in 7 noncontiguous dermatomes have been reported.

Zoster sine herpete

VZV infection may reactivate without causing cutaneous vesicles. These patients have severe dermatomal pain, possible motor weakness and possible hypesthesia, but no visible rash or vesicles.

Studies show that VZV infection may present as acute peripheral facial palsy in 8-25% of patients who have no cutaneous vesicles. This is more common in immunosuppressed patients who use acyclovir (or other agents) as zoster prophylaxis.[1]

Myelitis

VZV infection may also cause central nervous system deficits.

Although deficits are more common in immunocompromised individuals, such presentations do occur in the general population.

In one report, the condition began as a typical shingles rash, but spinal cord involvement became apparent 3 weeks after the onset of the initial rash.

The manifestations are usually bilateral. The physical findings may progress.

The underlying pathology typically progresses for 3 or more weeks. Progression for 6 months in immunocompromised individuals has been reported.

With intravenous acyclovir treatment, most cases fully resolve. Recurrence is rare but has been reported.

Zoster encephalitis is also rare but is reported in otherwise healthy individuals. Due to the effectiveness of 2-dose vaccinations, fewer cases of VZV encephalitis occur,[3] yet most cases in vaccinated individuals are due to wild type from the vaccine strain.[4]

Ramsay-Hunt syndrome

This syndrome occurs when the geniculate ganglion is involved.

The clinical presentation includes a peripheral facial palsy, pain in the ear and face, and vesicles in the external ear canal.

Additional auditory and vestibular symptoms may be present. The vesicles are not present in all cases.

Keratitis (herpes ophthalmicus)

This is caused by reactivation of VZV infection in the ophthalmic division of the trigeminal nerve.

The presentation may include conjunctivitis or corneal ulcers. Complications include blindness.

The vesicles do not have to be present.

Rarely, in cases of herpes ophthalmicus, the virus migrates along the intracranial branches of the trigeminal nerve, causing thrombotic cerebrovasculopathy with severe headache and hemiplegia.

Causes

Immunosuppression increases the risk of both typical shingles and atypical presentations, such as myelitis, encephalitis, disseminated disease, and visceral involvement.

Laboratory Studies

When the presentation includes the typical dermatomal rash, additional studies are not required.

If the diagnosis is in doubt, a Tzanck smear can be performed and has a sensitivity of about 60%. To obtain a Tzanck smear, remove the crust from a vesicle and scrape the underlying moist skin with a No. 15 surgical blade. Smear the cells from the vesicle base onto a slide, fix for 1 minute with absolute alcohol, and stain with Wright stain (other staining methods can also be used).

The diagnosis can also be confirmed with a culture of vesicular fluid that is positive for varicella-zoster virus (VZV).

In cases of zoster sine herpete, DNA analysis via polymerase chain reaction (PCR) can be used for early diagnosis if laboratory turnaround time is reasonably short. If not, the decision of whether to start empiric acyclovir must be based on clinical grounds alone.

In cases of acyclovir-resistant VZV, detections of mutations in thymidine kinase can be determined by PCR and sequence analysis. Acyclovir-resistance may occur in stem cell transplant recipients.[5]

Imaging Studies

MRI may be useful if myelitis or encephalitis is suspected.

Procedures

Lumbar puncture may be helpful if signs suggest myelitis or encephalitis. The cerebrospinal fluid (CSF) shows increased levels of protein and pleocytosis because the inflammatory response involves the leptomeninges. CSF PCR can be used to detect VZV DNA.

Although seldom necessary, biopsy results provide a definitive diagnosis.

Histologic Findings

The varicella zoster virus is a DNA virus with a genome that encodes 70 proteins.

The Tzanck preparation shows characteristic findings of giant cells with 2-15 nuclei. Recently infected epithelial cells contain a single enlarged nucleus with a thick nuclear membrane.

After reactivation, meningeal biopsy samples show a local inflammatory response, consisting of plasma cells and lymphocytes, that encompasses the leptomeninges.

Evidence has shown that motor neuron involvement is demyelinating rather than axonal.

Medical Care

Treatment options are based on the patient's age, immune state, duration of symptoms, and presentation.

Several studies indicate that antiviral medications decrease the duration of symptoms and the likelihood of postherpetic neuralgia, especially when initiated within 2 days of the onset of rash. In typical cases that involve individuals who are otherwise healthy, oral acyclovir may be prescribed. An important study by Kubeyinje (1997) suggested that the use of acyclovir in healthy young adults with zoster is not clearly justified, especially in situations of limited economic resources.[6]

Acyclovir has 2 limitations—bioavailability and the existence of some resistant strains of varicella-zoster virus (VZV).

Other medications, including valacyclovir, penciclovir, and famciclovir, are also available. They may have an increasing role in the treatment of typical zoster. Studies suggest that, when compared with oral acyclovir, the new medications may decrease the duration of the patient's pain.

Varicella zoster immune globulin (VariZIG) is indicated for administration to high-risk individuals within 10 days (ideally within 4 days) of chickenpox (varicella zoster virus) exposure.[2]  

In July 2013, the CDC issued updated recommendations for the use of varicella-zoster immune globulin (VariZIG) to reduce the severity of VZV infection, extending the window for postexposure prophylaxis for those at high risk for severe varicella.[7, 8]  The FDA's original approval of VariZIG recommended use within 4 days, but subsequent studies have shown that the treatment is effective for up to 10 days after exposure.

Other recommendations include the use of VariZIG in the following patients:

Dworkin et al (2009) conducted a randomized, placebo-controlled trial of oral oxycodone and oral gabapentin as potential treatments for acute pain in patients with herpes zoster. They found that controlled-release oxycodone was superior to placebo in the early period of pain (1-14 d). Gabapentin was not shown to yield a significantly greater relief of pain than placebo, although it conferred modest pain relief during the first week.[9]

Surgical Care

Surgical care may be required for complications of zoster, such as necrotizing fasciitis.

Consultations

Consultation with a neurologist is indicated in cases of myelitis or encephalitis.

Consultation with an infectious disease specialist may be helpful if bacterial superinfection or viral resistance to acyclovir is evident.

Consultation with an ophthalmologist is indicated upon optic involvement.

Consultation with a dermatologist may be helpful when the rash is atypical.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Current research is considering whether the varicella vaccine may also prove efficacious as treatment for active varicella-zoster virus (VZV) infection.

Acyclovir (Zovirax)

Clinical Context:  Patients experience less pain and faster resolution of cutaneous lesions when used within 48 h from rash onset. May prevent recurrent outbreaks.

Valacyclovir (Valtrex)

Clinical Context:  Prodrug rapidly converted to the active drug acyclovir. More expensive but has a more convenient dosing regimen than acyclovir.

Famciclovir (Famvir)

Clinical Context:  Prodrug that, when biotransformed into active metabolite penciclovir, may inhibit viral DNA synthesis/replication.

Class Summary

Three medications may help reduce pain and symptoms and the incidence of postherpetic neuralgia. All need to be used with caution in patients with renal compromise. Hemolytic uremic syndrome is rare but has been reported. All 3 agents may be used for 7-10 d, depending on response. Only acyclovir is available in an intravenous form.

Varicella virus vaccine (Varivax)

Clinical Context:  A live attenuated varicella virus prepared from the Oka/Merck strain. It is propagated in human diploid cell cultures (MRC-5). Each 0.5-mL dose (when reconstituted) contains 1350 PFU of varicella, sucrose, and gelatin; residual components of MRC-5 DNA and protein; and trace quantities of neomycin and fetal bovine serum. Indicated for vaccination against varicella in individuals >1 y.

Varicella zoster vaccine (Zostavax)

Clinical Context:  This is a lyophilized preparation of the Oka/Merck strain of live, attenuated varicella-zoster virus (VZV). It has been shown to boost immunity against herpes zoster virus (shingles) in older patients. It reduces the occurrence of shingles in individuals older than 60 years by about 50%. For individuals aged 60-69 years, it reduces the occurrence by 64%. In the ZEST trial, the vaccine significantly reduced the risk by 70% in subjects aged 50-59 years. It also slightly reduces pain compared with no vaccination in those who develop shingles. It is indicated for the prevention of herpes zoster in patients who have no contraindications.

Class Summary

These agents are used to induce active immunity.

The combined MMRV vaccine (ProQuad) has been shown to be associated with an increased risk of febrile seizure occurring 5-12 days following vaccination at a rate of 1 in 2300-2600 in children aged 12-23 months compared with separate MMR vaccine and varicella vaccine administered simultaneously.[10, 11] As a result, the CDC Advisory Committee on Immunization Practices (ACIP) recommends that separate MMR and varicella vaccines be used for the first dose, although providers or parents may opt to use the combined MMRV for the first dose after counseling regarding this risk.[12] MMRV is preferred for the second dose (at any age) or the first dose if given at age 48 months or older.

Data from postlicensure studies do not suggest that children aged 4-6 years who received the second dose of MMRV vaccine had an increased risk for febrile seizures after vaccination compared with children the same age who received MMR vaccine and varicella vaccine administered as separate injections at the same visit.[12]

Capsaicin transdermal patch (Qutenza)

Clinical Context:  Transient receptor potential vanilloid-1 (TRPV1) agonist indicated for neuropathic pain associated with postherpetic neuralgia. TRPV1 is an ion channel–receptor complex expressed on nociceptive skin nerve fibers. Topical capsaicin causes initial TRPV1 stimulation that may cause pain, followed by pain relief by reduction in TRPV1-expressing nociceptive nerve endings. Neuropathic pain may gradually recur over several months (thought to be caused by TRPV1 nerve fiber reinnervation of treated area).

Class Summary

Topical analgesics that contain capsaicin are effective in decreasing neuropathic pain caused by postherpetic neuralgia.

Varicella zoster immune globulin, human (VariZIG)

Clinical Context:  Varicella zoster immune globulin (VZIG) contains immunoglobulin G (IgG) varicella-zoster antibodies. It provides passive immunization to exposed individuals at high risk of complications from varicella. High- risk groups include immunocompromised children and adults, newborns of mothers with varicella shortly before or after delivery, premature infants, infants < 1 year, adults without evidence of immunity, and pregnant women. Administer by deep IM injection, preferably in deltoid muscle. For neonates or infants, administer IM in anterolateral aspect of thigh.

Class Summary

The specific immune globulin with IgG varicella zoster antibodies provides passive immunization for susceptible individuals when administered within 10 days (ideally within 96 hours) of exposure.

Further Outpatient Care

Typical cases of zoster may be treated in the outpatient setting.

Initial evaluation should address the possibility of atypical manifestations.

Further Inpatient Care

Patients with ocular involvement may be treated in the hospital.

Inpatient treatment may be appropriate for people who develop complications.

The main patient complaint is pain.

Inpatient treatment is appropriate for immunocompromised people or those with atypical presentations, including myelitis.

Deterrence/Prevention

In May 1995, the American Academy of Pediatrics reviewed the literature on the safety and effectiveness of varicella vaccine and recommended that all susceptible children and adolescents without a contraindication receive routine varicella vaccination. They reaffirmed this recommendation in January 2000. However, many logistic and financial barriers have prevented the widespread adoption of this recommendation.

Both clinical varicella and zoster may occur despite vaccination. However, in 3 large studies, vaccination was 100% effective in preventing severe disease.

A study by Tseng et al examined the risk of herpes zoster in patients who underwent vaccination.[13] Among older adults (>60 y), a lower incidence rate was noted.

In March 2011, the Food and Drug Administration (FDA) lowered the approved age for use of Zostavax to 50-59 years. Zostavax was already approved for use in individuals aged 60 years or older. Annually, in the United States, shingles affects approximately 200,000 healthy people aged 50-59 years. Approval was based on a multicenter study, the Zostavax Efficacy and Safety Trial (ZEST).[14] The trial was conducted in the United States and 4 other countries in 22,439 people aged 50-59 years. Participants were randomized in a 1:1 ratio to receive either Zostavax or placebo. Participants were monitored for at least 1 year to see if shingles developed. Compared with placebo, Zostavax significantly reduced the risk of developing zoster by approximately 70%.

The virus was found in the saliva of individuals who received the zoster vaccine; persons older than 60 years shed virus in their saliva for as long as 4 weeks after vaccination.[15]

Complications

In cases of typical zoster, both streptococcal and staphylococcal superinfections are common potential complications. With ocular, spinal cord, or other involvement, permanent injury is a risk. With ocular involvement, the patient may require long-term antiviral treatment. One study suggests that trigeminal distribution and advanced age increase risk of complications.[16]

Other complications include the following:

Prognosis

Postherpetic neuralgia remains the most common complication of varicella-zoster virus (VZV) infection reactivation, affecting up to 50% of the patients older than 60 years. Most cases are temporary, but many cases persist chronically, impairing productivity and quality of life.

A landmark study by Rowbotham and Fields (1996) shows no clear relationship between loss of peripheral nerve function and postherpetic neuralgia pain.[17] Although many mechanisms may cause the pain, this study helps explain the efficacy of topical agents such as capsaicin or lidocaine patches.

As evidence of the complexity of the issue, Oaklander and colleagues (1998) examined patients with postherpetic neuralgia and found bilateral damage in patients with unilateral shingles. Neurite loss was noted in the contralateral homologous region in test subjects who experienced no pain and had no history of shingles.[18]

Many treatment options are available for postherpetic neuralgia.

Patient Education

For excellent patient education resources, visit eMedicineHealth's Infections Center. Also, see eMedicineHealth's patient education articles Shingles and Chickenpox.

Author

Wayne E Anderson, DO, FAHS, FAAN, Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center

Disclosure: Received honoraria from Teva for speaking and teaching; Received grant/research funds from Allergan for other; Received honoraria from Insys for speaking and teaching; Received honoraria from DepoMed for speaking and teaching.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Gordon L Woods, MD, Consulting Staff, Department of Internal Medicine, University Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Program Director of Infectious Disease Fellowship, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Maria D Mileno, MD, Associate Professor of Medicine, Division of Infectious Diseases, The Warren Alpert Medical School of Brown University

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of prior coauthor Amar Safdar, MD, to the development and writing of this article.

References

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Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.

Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.

Human herpesvirus (HHV) type 3. Intraoral herpes zoster closely resembles recurrent HHV-1 infection, but the lesions generally follow a dermatome and stop sharply at the midline, as shown here. However, the rules for common sites of occurrence of HHV-1 and HHV-3 often do not apply to patients who are immunocompromised. Courtesy of Sheldon Mintz, DDS.

Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.

Human herpesvirus (HHV) type 3. Intraoral herpes zoster closely resembles recurrent HHV-1 infection, but the lesions generally follow a dermatome and stop sharply at the midline, as shown here. However, the rules for common sites of occurrence of HHV-1 and HHV-3 often do not apply to patients who are immunocompromised. Courtesy of Sheldon Mintz, DDS.