Assay Sheet

Test ID

9500 Varicella-Zoster Virus (VZV) Real-time qPCR

CPT Code

Clinical Utility

VZV reactivation is commonly seen in immunocompromised individuals. These patients are more likely to have disseminated disease with extensive skin lesions, pneumonia, hepatitis or encephalitis. Proper management is dependent upon early diagnosis; quantitative DNA PCR is a rapid and sensitive tool useful for detecting the virus, tracking the course of the infection, and monitoring response to treatment.

Procedure

Extraction of varicella-zoster viral DNA from plasma, CSF, other biological fluids, or tissues followed by amplification and detection using real-time, quantitative PCR. An internal control is added to ensure the extraction was performed correctly and the PCR reaction was not inhibited.

Specimens

CSF: 1 ml fluid frozen; submitted in a sterile, leakproof tube; ship on dry ice.
Swab: Sterile swab placed in 1-2 ml sterile saline; do not use viral transport media.
Whole Blood: 3-5 ml submitted in an EDTA tube; ship ambient.
Other: Please inquire.

Specificity

The primers and probes used in this assay are specific for VZV based on similarity search algorithms. Additionally, no cross reactivity was detected when tested against adenoviruses, BKV, CMV, EBV, HSV-1, HSV-2, HHV-6 variant A, HHV-6 variant B, HHV-7, HHV-8, JCV, parvovirus B19, and SV-40.

Varicella-Zoster Virus Assay Range

100 copies/ml to 1 x 10¹⁰ copies/ml

Turnaround Time

Within 24 hours of receiving specimen

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PCR tests are performed pursuant to a license agreement with Roche Molecular Systems, Inc.
This assay was developed and the performance characteristics were determined at ViraCor Laboratories. This test is performed in a CLIA certified laboratory. FDA approval is not required for the performance of this test.
AS03-0108

Pathogen Overview

ABOUT THE VARICELLA-ZOSTER VIRUS

Varicella-zoster virus (VZV) was isolated and characterized in 1958, although it has been recognized as the cause of both varicella (chicken pox) and herpes zoster (shingles) for over 100 years. VZV is one of eight herpesviruses that has been found to affect humans; the others include: HSV-1, HSV-2, CMV, EBV, HHV-6, HHV-7 and HHV-8. The herpesvirus family is divided into three subfamilies; HSV-1, HSV-2 and VZV comprise the Alphawvirinae subfamily. The virus contains a linear, double-stranded DNA molecule and has a lipid containing envelope. All members of the herpesvirus family share the ability to establish a lifelong latency in their host.

VARICELLA-ZOSTER VIRUS CLINICAL MANIFESTATIONS

Varicella and zoster are both caused by VZV, but are actually two distinct clinical conditions. More than 90% of the population develops a clinical or serological varicella infection by adolescence, and virtually 100% of the population by age 60. Asymptomatic infections of VZV are not uncommon, therefore, individuals reporting a negative history for varicella should have their VZV serostatus evaluated. VZV infections are medically significant, causing approximately 4 million cases of varicella (prior to advent of the vaccine) and 500,000 cases of zoster each year.

Varicella is highly contagious, with an incubation period of approximately 14 days. The virus is typically spread by airborne transmission, droplet or contact with vesicle fluid. The host is typically infected through viral contact with the mucosa of the upper respiratory tract or the conjunctiva. Patients become contagious 2 days prior to manifestation of the rash, and remain so until all lesions are crusted.

Varicella infection in an immunocompetent child is characterized by a rash, low-grade fever and general malaise. The skin subsequently develops maculopapules, vesicles and scabs. These evolve throughout the course of the disease, develop scabs and fall off within 1-2 weeks after onset
of infection.

Immunocompromised children have many more skin eruptions, and healing time is roughly 3 times longer than for immunocompetent children. These children are at a much greater risk for developing visceral complications of the lungs, liver and central nervous system. These complications occur in approximately 30-50% of cases, and may be fatal in up to 15% of cases. Immunocompetent adults who develop varicella are at risk of developing encephalitis, which can be life-threatening. Approximately 30% of adult varicella patients are hospitalized for varicella pneumonia. Myocarditis, nephritis, bleeding diatheses and hepatitis are other non-cutaneous sites of involvement.

When VZV reactivates, it is known as zoster. 10-20% of all people will develop zoster, an incidence that increases dramatically with advanced age. Unfortunately, many individuals will also develop post-herpetic neuralgia, requiring long-term medical care. Zoster typically causes diffuse, varicella-like skin lesions, most often on the chest and back and occasionally around the eye. Patients usually experience pain 48-72 hours before the lesions appear, in the areas that will become affected. In an immunocompetent individual, lesions form over a period of 3-5 days. The disease lasts approximately 10-15 days, however, the skin may not return to normal for up to 1 month. Post herpetic neuralgia is common; therefore, zoster is generally treated with acyclovir, even in immunocompetent individuals. When lesions occur in the trigeminal nerve area, medical treatment should be sought immediately to avoid spread of lesions into the eye and potential loss of vision.

In immunocompromised individuals, zoster can be much more serious. It may take up to 2 weeks for lesions to form, which may not scab over for 3-4 weeks. Due to rare occurrences of immunocompetent individuals under 45 years of age developing reactivated VZV, patients in this age group with zoster should be evaluated for the possible presence of HIV infection. As many as 30% of males with HIV will develop zoster at least one time in the 12 month period following diagnosis; they are at particular risk for complications, such as VZV retinitis, acute renal necrosis and chronic, progressive encephalitis. Another potential complication for HIV patients is chronic zoster, in which new lesions continue to form and existing lesions do not heal.

A live attenuated vaccine is now available. It has been shown to be about 90% effective for several years in preventing varicella symptoms with a single injection. It is somewhat less effective in immunocompromised children, but has dramatically reduced the morbidity and mortality from community acquired varicella infection. In healthy children, the vaccine may produce a few skin papules. This occurs much more frequently in immunocompromised children who may actually develop mild varicella. The attenuated vaccine can still establish latency in the dorsal ganglia and lead to zoster in later years, however, this occurs with less frequency than following natural varicella infection.

VARICELLA-ZOSTER VIRUS LABORATORY DIAGNOSIS

A diagnosis of varicella or zoster in an immunocompetent individual is typically made based upon the patient’s history and a physical examination. The characteristic skin lesions and their location are generally sufficient for a clinical diagnosis. In certain populations, such as the immunocompromised, VZV infections can cause potentially life-threatening complications. Because the course of the infection can vary from that in an immunocompetent individual, laboratory confirmation is recommended in these patients. While the virus will grow in cell culture, it is not the diagnostic method of choice due to lack of sensitivity and extended time frame required for the virus to grow. In these patients, molecular methods or immunofluorescence staining are a better choice. Quantitative real-time PCR has been shown to be a highly sensitive, accurate and rapid means to detect VZV from a wide variety of specimen sources. It is commonly used, not only to diagnose VZV infection, but also to establish the level of viral burden (viral load) and monitor the patient’s response to therapy.

VARICELLA-ZOSTER VIRUS TREATMENT

Acyclovir has been shown to effectively decrease lesion formation and improve healing time in both immunocompetent and immunocompromised patients, which may help to prevent life-threatening complications in the immunocompromised. High dose acyclovir can improve resolution times of lesions and reduce the risk of prolonged pain for immunocompetent patients with zoster. Oral medication options include high-dose oral acyclovir, valacyclovir or famciclovir. Immunocompromised patients should be carefully monitored for disease progression and the possible development of resistance. Valacyclovir and famciclovir have been shown to be more convenient than acyclovir, and of comparable or superior efficacy. IV acyclovir has been proven to prevent progression of disease in those patients who are more likely to develop disseminated disease.

Selected References

Cohen JI, Brunell PA, Strauss SE, Krause PR. Recent advances in Varicella-zoster virus infection. Ann Intern Med. 1999;(130):922-932.

Gnann JW. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186(suppl 1):S91-98.
Liesgang TJ. Varicella-zoster viral disease. Mayo Clinic Proc. 1999;(74):983-998.

Whitley R. Varicella-zoster virus. In: Mandell GL, Bennett JE, Dolin, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Vol 2. 4th ed. New York, NY: Churchill Livingstone; 1995:1345-1351.

PAO-14 -0707 PCR tests are performed pursuant to a license agreement with Roche Molecular Systems, Inc.

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Collection & Shipping

PCR tests are performed pursuant to a license agreement with Roche Molecular Systems Inc.
ImmuKnow is a registered trademark of Cylex Incorporated.
Respiratory Viral Panel is a product of Luminex Corporation.

Abstracts & Publications

Cohen JI, Brunell PA, Strauss SE, Krause PR. Recent advances in varicella-zoster virus infection. Ann Intern Med. 1999;(130):922-932.

Varicella-zoster virus has developed a complex strategy that shows it to remain latent in the body and avoid destruction by the immune system. Although varicella and zoster have been recognized since antiquity, several new clinical syndromes-including chronic chickenpox with persistent verrucous lesions and disseminated varicella without skin lesions-have been noted in patients with AIDS. Acyclovir has been the mainstay for treating severe varicella-zoster virus infections; however, newer antiviral agents, including valacyclovir and famciclovir, have expanded therapeutic options for treating adults with herpes zoster. The recently licensed live attenuated vaccine for varicella-zoster virus is effective in preventing chickenpox, and the vaccine's ability to stimulate immunity in seropositive adults suggests a promising strategy with which to modify the course of herpes zoster.

Gnann JW. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186(suppl 1):S91-S98.

Varicella-zoster virus (VZV) is the etiologic agent of varicella (primary infection) and herpes zoster (reactivation of latent infection). Although varicella is most often a relatively benign and self-limited childhood illness, the disease can be associated with a variety of serious and potentially lethal complications in both immunocompetent and immunocompromised persons. One complication of varicella that appears to be increasing in frequency is serious bacterial soft tissue infections caused by group A streptococci. Issues relating to management of varicella become especially complex when varicella involves pregnant women or susceptible neonates. Herpes zoster can be associated with a variety of neurologic complications, including a syndrome of delayed contralateral hemiparesis. Neurologic complications of herpes zoster, including chronic encephalitis, occur with increased frequency in AIDS patients. VZV retinitis is a potentially sight-threatening complication that occurs in both immunocompetent and immunocompromised persons. Current knowledge regarding pathogenesis and antiviral therapy is reviewed.

Liesgang TJ. Varicella-zoster viral disease. Mayo Clin Proc. 1999;(74):983-998.

Herpes zoster is a cause of considerable morbidity, especially among elderly patients. Substantial research on the biology of the varicella zoster virus has led to advances in our knowledge of the pathophysiology of the disease along with more successful therapy for the acute episodes of herpes zoster. Ophthalmic zoster is more common than zoster in other cranial nerves and is associated with pronounced suffering. This article reviews the epidemiology, biology, and latency of herpes zoster, discusses the pathophysiology of the disease, and describes treatment options with antivirals and corticosteroids. The pathophysiology and treatment options for postherpetic neuralgia are also addressed. The varicella vaccine is now available, and initial results suggest that this may lessen the effect of herpes zoster in the future.

Whitley R. Varicella-zoster virus. In Mandell GL, Bennett JE, Dolin, eds. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol 2. 4th ed. New York, NY: Churchill Livingstone; 1995:1345-1351.

This chapter appears in the 2nd volume of the definite textbook on infectious diseases. Chapter 116 of the text describes the history, pathogen and replication, epidemiology, pathogenesis, clinical manifestations, diagnosis, therapy and prevention of varicella-zoster virus.