Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (509 page)

   Clinical disease typically occurs about 14 days after exposure. Most patients with primary varicella show an abrupt onset with the appearance of asynchronous “crops” of vesicular lesions appearing over several days, mainly on the head and trunk. Lesions at various stages, papular, vesicular, ulcerative, and crusted, are all seen at any time during active infection. Fever and nonspecific symptoms may occur. Lesions typically heal without scar formation.

   The most common complication of primary varicella is bacterial superinfection, especially with
Streptococcus pyogenes
. Although involvement of the respiratory tract may occur in a significant minority of patients, clinically significant pneumonia is an uncommon, but potentially serious, complication in a small number of patients, especially adults. Meningoencephalitis, cerebellar ataxia, and other CNS complications occur rarely. Hemorrhagic varicella is an uncommon complication in immunocompetent patients.

   Zoster occurs, mainly in the elderly, decades after primary VZV infection. It usually presents with a localized, unilateral eruption of vesicles restricted to one or several adjacent dermatomes, reflecting the role of dorsal root or cranial nerve ganglia as the source of viruses. Aseptic meningitis with minimal CSF abnormalities may be seen in patients with zoster. Most patients recover spontaneously within 2 weeks. Localized cutaneous HSV infection may mimic zoster.

   Postherpetic neuralgia is a common complication of zoster and may develop in a significant minority of elderly patient after resolution of the rash. Motor deficits occur at the affected dermatome in about 1% of patients. This may manifest as bladder dysfunction or intestinal ileus. Zoster related to cranial nerves may result in retinitis or other ocular abnormalities, Ramsay Hunt syndrome, facial palsies, or other abnormalities of cranial nerve function.

   Congenital varicella syndrome may occur in maternal infections during the first or early trimester of pregnancy. The embryopathy is manifested primarily by skin scars, limb atrophy, ocular abnormalities, mental retardation, or fetal loss. Maternal varicella after 20 weeks of gestation is usually not associated with congenital varicella syndrome, although “silent” infection occurs in the fetus. When maternal infection occurs between 2 and 5 days prior to delivery, however, severe neonatal varicella may develop.

   Laboratory Findings

The diagnosis of varicella and zoster can accurately be made clinically. Laboratory testing is usually required only for immunocompromised patients or patients with atypical disease. See the various diagnostic tests for Varicella-Zoster in Chapter
17
, Infectious Disease Assays.

Culture
: VZV may be reliably isolated by cell culture of vesicle fluid or scrapings from the base of wet ulcerative lesions. Culture results are usually positive after 3–5 days. The sensitivity of viral culture of CSF and other specimen types is lower.

NAAT
: Standard and real-time PCR methods may be used for diagnosis of acute VZV infections. Molecular diagnostic methods provide sensitive and specific results for a variety of types of specimens.

Serology
: Humoral and cell-mediated responses are brisk after primary infection, occurring within several days of clinical disease. Levels peak within 3 months and then decline but are detectable for years. A bump in specific antibody subsets may be seen in patients after an outbreak of zoster.

   A positive IgM result or fourfold or greater increase in VZV IgG or total antibody titer in acute and convalescent samples is diagnostic of VZV infection. Silent fetal infection may be inferred by persistence of positive VZV antibody titers beyond 8 months of life.

   The fluorescent antibody to membrane antigen assay (FAMA) is the most sensitive assay, if available, to document immunity after natural infection or vaccination. Detection of VZV antibodies in CSF is diagnostic of aseptic meningitis, even without skin lesions.

Histology
: Demonstration of specific VZV antigen by immunofluorescent staining of cells from vesicular lesions is diagnostic of acute VZV infection and is more sensitive than viral culture. DFA testing allows prompt diagnosis.

Core laboratory
: Core laboratory tests are generally not required unless severe disease is present. Clinical or subclinical hepatitis may occur in primary or systemic VZV infections. Elevation of transaminases, without hyperbilirubinemia, is typical. WBC count is usually decreased with absolute and relative lymphocytosis early in primary infection. Thrombocytopenia may be seen, especially in severe disease.

CSF findings
: In patients with CNS complications of VZV infection, the CSF parameters are usually normal or only mildly abnormal. Forty percent of zoster patients show increased cells (<300 mononuclear/μL) in CSF.

Suggested Readings

Arvin AM. Varicella-Zoster virus.
Clin Microbiol Rev.
1996;9:361–381.

Bonnez W. Chapter 28, Papillomavirus. In: Richman DD, Whitley RJ, Hayden FG.
Papillomavirus in Clinical Virology
, 3rd ed. Washington, DC: ASM Press; 2009.

Cohen JI. Epstein-Barr virus Infection.
N Engl J Med.
2000;343:481–492.

Corey L, Wald A. Maternal and neonatal herpes simplex virus infections.
N Engl J Med.
2009;361:1376–1385.

Crough T, Khanna R. Immunobiology of human cytomegalovirus: from bench to bedside.
Clin Microbiol Rev.
2009;22:76–98.

Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis.
N Engl J Med.
2009;361: 1776–1785.

Gnann JW, Whitley RJ. Herpes zoster.
N Engl J Med.
2002;347:340–346.