Diagnosis of varicella-zoster virus infection

INTRODUCTION — Varicella-zoster virus (VZV) infection causes two clinically distinct forms of disease. Primary infection with VZV results in varicella (chickenpox), characterized by vesicular lesions in different stages of development on the face, trunk, and extremities. Herpes zoster, 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.

The diagnosis of these two diseases is usually made clinically. However, the use of diagnostic assays may be important in specific situations, as discussed below.

The clinical manifestations of chickenpox and shingles are discussed elsewhere. (See "Treatment of herpes zoster" and "Clinical features of varicella-zoster virus infection: Chickenpox" and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

GENERAL BACKGROUND — The diagnosis of VZV infection is usually a clinical diagnosis based on the characteristic vesicular lesions, which are seen widespread in chickenpox (varicella) or in a restricted dermatomal pattern with associated neuritis in shingles (herpes zoster).

However, additional diagnostic information may be useful in the following situations:

●Atypical rash in an immunocompromised host

●Possible disseminated disease in an immunosuppressed host without cutaneous lesions

In addition, serologic testing may be necessary to determine if an individual at increased risk for varicella requires immunization (eg, a healthcare worker born after 1980 who does not have a history of childhood infection).

POLYMERASE CHAIN REACTION — The real-time polymerase chain reaction (PCR) assays provide confirmation of VZV from clinical specimens obtained from skin lesions and selected body fluids such as CSF and bronchoalveolar lavage [1,2]. In a study comparing viral culture isolation to real-time PCR [2], 110 clinical specimens from dermal lesions were analyzed using both methods. VZV was isolated by culture in 15 samples (14 percent) and VZV DNA was detected by PCR in 51 (46 percent) samples. In another study that evaluated 1479 clinical specimens from 1220 patients with suspected herpes zoster, real-time PCR testing was highly sensitive compared with culture (92 versus 53 percent) [3]. In addition, PCR-based testing was highly specific; no cross-reactivity was identified when tested against several other herpesviruses.

Real-time PCR allows for rapid viral amplification, limits risk of contamination, confers superior sensitivity in isolating VZV from an array of clinical specimens, and affords more rapid turnaround time compared with conventional culture techniques.

PCR testing is also useful for a variety of other indications, such as making a diagnosis in a patient with vaccine-modified infection [4]. PCR testing of serum or blood may also be helpful in the transplant patient who has visceral disease prior to the appearance of cutaneous lesions [5].

DIRECT FLUORESCENT ANTIBODY — Rapid diagnosis of VZV infection can sometimes be accomplished by using direct fluorescent antibody (DFA) testing on scrapings from active vesicular skin lesions that have not yet crusted. The DFA test is widely available; it has lower cost compared to culture, and is associated with more rapid turnaround time [6,7]. One DFA assay can simultaneously detect HSV and VZV with a 1.5 hour turnaround time [6]. However, the sensitivity of DFA is often limited by the quality of the specimen; sufficient infected skin cells must be present on the slide to ensure a valid test.

VIRAL CULTURE — Virus isolation by culture is sometimes available but is insensitive and associated with low yield (approximately 50 to 75 percent) when compared with PCR testing [3,8,9]. Specific VZV culture isolation from a swab of vesicular skin lesion or sterile body fluid, such as CSF, typically requires prolonged incubation with a turnaround time of one to two weeks [6]. Sensitivity of culture also declines when lesions progress beyond the vesicular stage.

SEROLOGIC TESTING — The presence of IgG antibodies to VZV correlates both with a history of varicella and protection against subsequent infection. Serologic testing has been employed in health care workers to assess susceptibility related to their potential risk of exposure. Serologic testing has also been employed in vaccine studies to assess response to immunization.

Many different antibody tests are available with a wide range of performance standards [10]. The fluorescent antibody to membrane antigen (FAMA) is the most extensively validated assay and correlates best with susceptibility to and protection against varicella [11]. However, this test is not widely used because it is labor intensive and requires expert interpretation.

Many commercially available ELISAs are available that are considered generally less sensitive than FAMA, although specificity appears comparable [10]. Persons 60 years of age and older may not have been exposed to varicella for many years; consequently, waning antibodies may lead to a false-negative result and result in misclassification of the person as susceptible. In contrast, latex agglutination testing has been associated with false-positive test results and failure to vaccinate susceptible healthcare workers, who subsequently developed varicella after exposure [12].

Some experts have concluded that commercial ELISA assays are suitable for screening for VZV susceptibility among healthcare workers [10]. The rationale for this is that the risk of vaccinating an adult with a false-negative test result is much lower than the risk of natural infection in an individual falsely identified as seropositive.

Routine screening for varicella in individuals born in the United States before 1980, who are not healthcare workers, is not recommended because of extremely high rates of seropositivity in this population.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Varicella-zoster virus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Shingles (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Varicella-zoster virus (VZV) infection causes two clinically distinct forms of disease. Primary infection with VZV results in varicella (chickenpox), characterized by vesicular lesions in different stages of development on the face, trunk, and extremities. Herpes zoster (shingles) results from reactivation of endogenous latent VZV infection and is characterized by a painful, unilateral vesicular eruption. (See 'Introduction' above.)

●VZV infection is usually a clinical diagnosis based on the characteristic vesicular lesions, which are seen widespread in chickenpox (varicella) or in a restricted dermatomal pattern with associated neuritis in shingles (herpes zoster). No further diagnostic testing is necessary in a patient with typical clinical presentation. (See 'General background' above.)

●Additional diagnostic testing may be useful when considering VZV in an immunocompromised host or in the evaluation of atypical lesions. (See 'General background' above.)

●When further testing is needed, real-time PCR allows viral amplification of VZV from an array of clinical specimens and affords more rapid turnaround time compared to conventional culture techniques. (See "Polymerase chain reaction (PCR)".)

●Rapid diagnosis of VZV infection can also be accomplished by using direct fluorescent antibody (DFA) on scrapings from active vesicular skin lesions that have not yet crusted. (See 'Direct fluorescent antibody' above.)

●Virus isolation by culture is associated with low yield and requires prolonged incubation. (See 'Viral culture' above.)

●Serologic testing with ELISA is used to determine susceptibility to varicella and the need for immunization. Testing is not necessary in individuals born in the United States before 1980 due to the high rates of seroprevalence among this age group. (See 'Serologic testing' above.)