Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (496 page)

   Immunocompetent patients who develop acute disease most often present with a mononucleosis syndrome with pharyngitis, lymphadenopathy, and splenomegaly. Laboratory studies may show elevated atypical lymphocytes and transaminases.

   Fetal and neonatal disease is the result of vertical transmission during acute or recurrent maternal infection. Neonatal infection may also be transmitted by breast milk. Most infected neonates are asymptomatic at birth but are at risk (10–15%) for development of hearing loss, learning disability, and/ or other organ dysfunction. Congenital CMV disease may manifest at birth with a variety of clinical features, alone or in combination, including intrauterine growth retardation, microcephaly, intracranial calcifications, hepatosplenomegaly, jaundice, retinitis, thrombocytopenia, and purpura.

   Disease in immunocompromised patients may be caused by acute, newly acquired infection or by reactivation of latent infection. CMV disease may cause life-threatening systemic or organ-specific disease. Primary infection poses the greatest risk for severe disease in immunocompromised patients, but there is also significant risk associated with CMV reactivation, especially in bone marrow transplant patients. Fever is a constant feature of disease. Other disease manifestations include CNS disease (encephalitis, polyradiculopathy), GI infection (colitis, esophagitis), hepatitis, myelosuppression/thrombocytopenia, pneumonitis, and retinitis.

   Transmission of CMV by blood transfusion and organ transplantation is well described.

   Laboratory Findings

Culture
: Routine viral culture provides strong evidence for viral replication in vivo and can be performed on a variety of specimen types. Cell cultures, however, may take up to 3-week incubation to provide final results. The shell vial technique, with early staining for proteins produced early in the CMV replicative phase using tagged monoclonal antibodies, markedly decreases turnaround time (48–72 hours) while maintaining good sensitivity. Within the first 2 weeks, viral culture of urine is the most sensitive and specific means for diagnosis of congenital CMV infection. Viral cultures of CSF are usually negative in CNS infections.

Antigenemia
: Tagged monoclonal antibodies may be used to detect CMV antigens associated with active replication. The CMV pp65 antigenemia assay can be used to detect active CMV replication associated with emerging or active disease in transplant patients with good sensitivity and specificity.

Molecular diagnostics
: Viral load testing has provided the most important indicator for the presence (or emergence) of active infection in immunocompromised patients. The viral load is directly proportional to the potential severity of disease. Low viral loads must be interpreted with caution because they may represent transient dysregulation of latent infection rather than progressive, active replication.

Histopathology
: Histopathologic examination demonstrates characteristic changes, including intranuclear and intracytoplasmic inclusions. Specimens may be stained using H&E, other nonspecific stain, or with specific immunologic or nucleic acid reagents.

Serology
: May be used to diagnose acute infection or to document immune status.

Core laboratory
: Laboratory findings due to predisposing or underlying conditions are seen. Characteristic laboratory changes are seen with infection of the liver, kidney, or adrenal gland.

ENCEPHALITIS VIRUSES

See Chapter
4
, Central Nervous System Disorders, for a discussion of encephalitis and causal viral pathogens.

ENTEROVIRUS, COXSACKIEVIRUS, AND ECHOVIRUS

   Definition

Coxsackieviruses and echoviruses are species in the genus
Enterovirus
, family
Picornaviridae
. Enteroviruses show broad serologic diversity. Enteroviruses are very stable in the environment, allowing them to survive for long periods in water and sewage. Humans are the only natural host for enteroviral infections. As the name implies, enteroviruses initiate infection in the intestines. Infection is usually acquired by fecal–oral transmission. Infections occur worldwide.

   Who Should Be Suspected?

Children are most frequently infected, although enterovirus infections occur in all ages. The humoral immune response seems to be most important for control of enteroviral infections; agammaglobulinemic patients are at risk for more severe or chronic disease. Common clinically significant disease syndromes include myocarditis disease, myalgia, pleurodynia, neonatal infection, aseptic meningitis, conjunctivitis, hand-foot-mouth disease, herpangina, and upper and lower respiratory tract infections.

   Laboratory Findings

Most enteroviral infections are mild and self-limited and may be diagnosed without specific laboratory testing. For severe disease, possible diagnostic tests include the following:

Viral culture
: Isolation of virus in culture has been the traditional method for specific diagnosis of enteroviral infection. Growth of specific enteroviruses is variable in different cell lines, and the pattern of growth in culture may provide preliminary presumptive identification for a specific group. Some group A coxsackieviruses do not grow in cell culture. Isolation of an
Enterovirus
species from CSF establishes a diagnosis of enteroviral meningitis. Although isolation of enteroviruses from stool or the nasopharynx is commonly seen in patients with severe enteroviral disease, like meningitis, positive cultures from these sites must be interpreted with caution: transient “colonization” may be seen unrelated to the clinical syndrome for which the specimen was collected.

Molecular diagnostic tests
: A number of commercially available diagnostic tests have been shown to provide very sensitive and specific detection of enteroviral infections. NAATs have proven to be especially useful to diagnose aseptic meningitis and help rule out bacterial meningitis in children presenting with fever and meningeal signs in summertime.