Varicella-Zoster Virus (VZV)

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 vesicular rash.

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.

VZV is a human alphaherpesvirus that causes varicella (chickenpox) as the primary infection and establishes latency in sensory ganglia. Infectious virus is transmitted by aerosolized respiratory droplets or by contact with virus in varicella or zoster skin lesions. VZV in respiratory or conjunctival mucosal cells can interact with and infect local immune system cells and those in adjacent lymphoid tissues. Chickenpox rash develops after an incubation period of 10 to 21 days.[6]

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, stress, 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.

United States

Varicella used to be very common in the United States. In the early 1990s, an average of 4 million people got varicella, 10,500 to 13,000 were hospitalized, and 100 to 150 died each year. Since introduction of the varicella vaccination program in 1995 in the United States, varicella morbidity (cases and hospitalizations) and mortality (deaths) have decreased by more than 90%.

Per CDC report, the incidence of herpes zoster is approximately 4 cases per 1,000 US population annually. The incidence among people 60 years and older is about 1 case per 100 US population annually. 

An estimated one million cases of herpes Zoster occur annually in the United States. 

A meta-analysis of 69 studies from various countries found a cumulative incidence of HZ ranging from 2.9 to 19.5 cases per 1,000 population and an incidence rate of HZ ranging from 5.23 to 10.9 cases per 1,000 person-years. Studies revealed a trend of increasing incidence of HZ with increasing age and over time.[7]

About 95% of patients with zoster experience severe pain during the illness. The risk of developing post herpetic neuralgia in patients with HZ varies from 5% to more than 30%, as recently reported in a systematic review of 130 studies in 26 countries.[8] The occurrence of both HZ and PHN increases with age.

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.

Severe complications include secondary bacterial infections (most notably those caused by group A beta-hemolytic Streptococcus, eg, cellulitis, necrotizing fasciitis, septicemia, and toxic shock syndrome), pneumonia, encephalitis, cerebellar ataxia, Reye syndrome, and death.[9]

The cumulative incidence (3.22–11.2 vs 2.44–8.0 cases per 1000 population) and incidence rates (6.05–12.8 vs 4.30–8.5 cases per 1000 person-years) were higher in females than males. Studies revealed a trend of increasing incidence of HZ with increasing age and over time.[7]

Zoster mortality is presumably elevated in countries severely affected by the HIV/AIDS pandemic.

The lifetime risk of developing HZ is between 25% and 30%, rising to 50% in those aged at least 80 years. The estimated average overall incidence of HZ is about 3.4–4.82 per 1000 person years, which increases to more than 11 per 1000 person years in those aged at least 80 years.[10]

Since the varicella vaccination program was implemented in 1995, hospitalizations and deaths from varicella have declined in the United States by 93% and 94%, respectively.

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.

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 in 1-2 days. 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.

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.

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 two unilateral dermatomes. Cases of zoster simultaneously occurring in seven 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.[2]

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 two-dose vaccinations, fewer cases of VZV encephalitis occur,[11] yet most cases in vaccinated individuals are due to wild type from the vaccine strain.[12]

Ramsay-Hunt syndrome

This syndrome occurs when the geniculate ganglion is involved.[4]

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.

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

Confirmation methods for lab testing are the following:

• PCR to detect VZV DNA from the base of a deroofed vesicular lesion is the most reliable and sensitive method, and is now considered the gold standard. False-negative PCR results are more likely to occur from lesions in vaccinated persons.
• Direct immunofluorescence (DFA) to detect VZV antigen is the second choice; sensitivity is only 60–70% of cases detectable by PCR.
• Viral culture of VZV is possible but is insensitive, time-consuming, and expensive because it requires special media.
• Serologic tests may be used to confirm disease but are less reliable than PCR or DFA for virus identification. A fourfold or greater rise in serum varicella IgG titers from acute- and convalescent-phase samples indicates a recent VZV infection. However, persons in whom vaccination produced a high VZV IgG titer may not achieve the required fourfold increase in the convalescent sample. Serologic tests are also less useful in immunocompromised people who are less likely to mount an effective immune response. Testing for VZV IgM by using commercial kits is not recommended because available methods lack sensitivity and specificity. 

MRI may be useful if myelitis or encephalitis is suspected.

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.

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 two to 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.

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

Several studies indicate that antiviral medications decrease symptom duration 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.[13]

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

Other medications, including valacyclovir, penciclovir, and famciclovir, also are 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.

Persistent lesions after 7 to 10 days of treatment with acyclovir may suggest acyclovir resistance. There are case reports of treatment with Foscarnet in immune compromised patients.[14] Infectious disease specialist consultation is recommended in complicated cases. Thymadine Kinase mutation testing and alternative treatment agents may be needed. 

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.[5]

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.[15, 16] 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:

• Immunocompromised patients without evidence of immunity
• Newborn infants whose mothers have varicella symptoms between 5 days before and 2 days after delivery
• Hospitalized premature infants born at 28 weeks of gestation or later whose mothers do not have evidence of immunity to varicella
• Hospitalized premature infants born at less than 28 weeks of gestation or who weigh less than 1000 g at birth, regardless of their mothers' evidence of immunity to varicella
• Pregnant individuals without evidence of immunity

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.[17]

There is no convincing evidence that use of corticosteroids prevents post herpetic neuralgia. 

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

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

Consultation with an infectious disease specialist should be considered if bacterial superinfection or viral resistance to acyclovir are suspected and for recurrent zoster. 

Consultation with an ophthalmologist is indicated upon optic involvement.

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

CDC recommends two doses of varicella (chickenpox) vaccine for children, adolescents, and adults to protect against varicella. Children are routinely recommended to receive the first dose at age 12 through 15 months and the second dose at age 4 through 6 years old.

In February 2018, the CDC approved the 2018 adult immunization schedules. Changes to the 2018 schedule regarding zoster vaccines includes the following[18, 19] :

• Administer two doses of recombinant zoster vaccine (RZV) (Shingrix) 2-6 months apart to adults aged 50 years or older regardless of past episodes of herpes zoster or receipt of zoster vaccine live (ZVL) (Zostavax).
• Administer two doses of RZV 2-6 months apart to adults who previously received ZVL at least 2 months after ZVL.
• For adults aged 60 years or older, administer either RZV or ZVL (RZV is preferred).

In October 2017, the FDA approved zoster vaccine recombinant, adjuvanted (Shingrix) for the prevention of shingles in adults aged 50 years or older. The approval is based on findings from a phase III clinical trial program assessing its efficacy, safety, and immunogenicity in 38,000 patients. Data from a pooled analysis of two clinical trials demonstrated efficacy against shingles at greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of 4 years.[20, 21]

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.

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.

Acyclovir (Zovirax)

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

Valacyclovir (Valtrex)

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

Famciclovir (Famvir)

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

Class Summary

These agents are used to induce active immunity.

The combined MMRV vaccine (ProQuad) is associated with an increased risk for febrile seizure occurring 5-12 days after 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.[22, 23]

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.[24]

MMRV is preferred for the second dose (at any age) or the first dose if given at age 48 months or older.

Data from post-licensure 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.[24]

Varicella virus vaccine (Varivax)

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.

Class Summary

These agents are used to induce active immunity.

In October 2017, the FDA approved zoster vaccine recombinant, adjuvanted (Shingrix) for the prevention of shingles in adults aged 50 years or older. The approval is based on findings from a phase III clinical trial program assessing its efficacy, safety, and immunogenicity in 38,000 patients. Data from a pooled analysis of two clinical trials demonstrated efficacy against shingles at greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of 4 years.[20, 21]

Zoster vaccine recombinant (Shingrix)

Non-live recombinant subunit vaccine intended for IM injection in 2 doses. It consists of glycoprotein E, an antigen, and AS01B, an adjuvant system, intended to induce a strong and sustained immune response to help overcome reduced immunity that comes with age. Indicated for the prevention of shingles (herpes zoster) in adults aged 50 years or older.

Class Summary

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

Capsaicin transdermal patch (Qutenza)

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

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.

Varicella zoster immune globulin, human (VariZIG)

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.

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

Initial evaluation should address the possibility of atypical manifestations.

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.

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.[25] 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).[26] 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.[27]

Severe herpes zoster has been described as a rare complication of varicella vaccination in immunocompetent young children, with these children at low risk of developing meningoencephalitis.[28] In children, VZV infection may produce a facial palsy[29] ; it may also result in zoster sine herpete, more so in children than in adults. Ramsay Hunt syndrome (herpes zoster oticus) tends to develop more often in school-aged children, while zoster sine herpete is more likely to develop in preschool children.

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.[30]

Other complications include the following:

• Necrotizing fasciitis

• Gastrointestinal complications

• Fatal hemorrhagic encephalitis

• Motor weakness

• Postherpetic neuralgia (most common) (The underlying pathophysiology of the condition may involve peripheral nerve injury or continued viral activation without rash, similar to zoster sin herpete.)

• Vasculopathy

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.[31] 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.[32]

Many treatment options are available for postherpetic neuralgia.

• Oral medications

• Topical preparations

• Gamma knife procedures

• Jaipur blocks

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