eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Cytomegalovirus Infection: Differential Diagnoses & Workup

Author: Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine
Contributor Information and Disclosures

Updated: May 8, 2008

Differential Diagnoses

Enteroviral Infections
Herpes Simplex Virus Infection
Herpesvirus 6 Infection
Lymphocytic Choriomeningitis Virus
Rubella
Toxoplasmosis

Other Problems to Be Considered

The differential diagnosis for CMV infection depends on the disease category, the age of the patient, and epidemiologic considerations.

In the neonate with congenital infection, the differential diagnosis includes any of the TORCH agents. Congenital toxoplasmosis may mimic congenital CMV infection but is much less common in the United States; however, in parts of Europe, particularly France and Belgium, congenital toxoplasmosis is a common and significant problem. In contrast to congenital CMV, the intracranial calcifications observed in congenital toxoplasmosis tend to be scattered diffusely throughout the brain and not in the classic periventricular distribution of CMV, which may be an important clue. Other congenital infections to be considered include lymphocytic choriomeningitis virus (LCMV) infection,¹¹ HSV infection, syphilis, enteroviral disease, HIV infection, and rubella.

In older patients, differentiating CMV infection from EBV infection may be clinically difficult. EBV is a more common cause of mononucleosis syndrome than CMV, and the heterophile antibody test results (ie, Monospot) are generally positive, allowing for ready differentiation of the diseases.

In immunocompromised patients, disease syndromes that are caused by CMV may be difficult to differentiate from other opportunistic infections. For example, CMV pneumonitis following bone marrow transplantation must be differentiated from Pneumocystis carinii infection and other viral infections, such as adenovirus and human herpesvirus 6 (HHV-6) infection. Appropriate diagnostic specimens obtained by studies such as bronchoalveolar lavage are indicated.

Workup

Laboratory Studies

• Viral culture
  • The most important diagnostic study in the evaluation of suspected cytomegalovirus (CMV) disease is the viral culture.
  • CMV may be cultured from virtually any body fluid or organ system. Blood, urine, saliva, cervicovaginal secretions, cerebrospinal fluid, bronchoalveolar lavage fluid, and tissues from biopsy specimens are all appropriate specimens for culture.
  • The specimen is inoculated onto human cells (usually human foreskin fibroblasts), and the cell culture is monitored for development of the characteristic CMV-associated cytopathic effect.
• Shell vial assay
  • Although culture is highly sensitive, clinical isolates of CMV may grow slowly, requiring as long as 6 weeks of incubation in the virology laboratory. An adaptation of tissue culture that provides results more rapidly is the centrifugation enhancement monoclonal-antibody culture technique, which is referred to as the shell-vial assay.
  • In this technique, the clinical specimen is centrifuged onto a cell monolayer (in effect, concentrating the specimen). Then, following incubation in tissue culture, cells are stained with a monoclonal antibody to a CMV-specific antigen, usually an immediate early gene product.
  • A positive shell vial culture is presumptive evidence of active CMV infection, and the test is a useful adjunct to traditional viral culture.¹²
• Exercise caution when obtaining and interpreting CMV diagnostic studies. Take special care in interpretation of diagnostic studies in infants. By definition, the diagnosis of congenital CMV infection requires identification of the virus in a culture specimen acquired before age 3 weeks because perinatally acquired infections may also begin to manifest at this time. Hence, a positive viral culture obtained in infants older than age 3 weeks may simply represent perinatal or breast milk acquisition and may not be interpreted as evidence of congenital CMV infection.
• Although theoretically helpful, CMV immunoglobulin M (IgM) assays are unfortunately too nonspecific to reliably diagnose congenital CMV. False-positive results are common; therefore, making the diagnosis of congenital infection outside of the immediate perinatal period is very difficult.
• Universal screening for congenital CMV infection may be a reasonable future goal and could enable establishment of appropriate anticipatory neurodevelopmental and serial audiological screening programs.
• Outside of the neonatal period, the major caution regarding CMV diagnosis is to use diagnostic studies appropriately to differentiate between CMV infection and CMV disease.
  • Infants and children infected with CMV may shed the virus for years, making a positive urine viral culture difficult to interpret.
  • Immunocompromised patients often have reactivation of latent CMV with subsequent viral shedding, even in the absence of overt CMV disease. Thus, the identification of CMV by culture in urine or saliva may reflect such chronic shedding of virus and is difficult to interpret in the evaluation of patients with end-organ disease, such as pneumonitis or hepatitis.
  • Lung biopsy or bronchoalveolar lavage may be necessary to confirm the diagnosis of CMV pneumonitis.
  • Hepatitis may require liver biopsy for confirmation of the diagnosis, and CMV hepatitis and chronic rejection may be a difficult differential diagnosis in liver transplant recipients, even with a biopsy.
• Newer molecular diagnostic studies, including polymerase chain reaction (PCR)¹³ and CMV antigenemia studies, are also useful and predictive in monitoring CMV disease activity in immunocompromised patients. The magnitude of the viral load in blood as determined by quantitative PCR in infants with congenital infection may predict neurodevelopmental outcomes and may be useful in monitoring response to antiviral therapy.

Imaging Studies

• Congenital
  • The most important study in the diagnostic evaluation of the congenitally infected infant with CMV is head CT scanning.
  • A CT scan of the head is required for infants with microcephaly or when congenital CMV infection is suspected because abnormalities in this study, particularly the presence of calcifications, have a strong positive predictive value and can aid in identifying children who need ongoing neurodevelopmental evaluation and therapy.
  • Recent evidence suggests that head ultrasonography may be of equal value to CT scanning in evaluation of potential intracranial pathology in the setting of congenital CMV.
  • Infants with congenital CMV infection may also require abdominal imaging studies (eg, ultrasonography, CT scanning) for documentation and monitoring of organomegaly.
• Other CMV syndromes
  • Depending on the patient population, radiographic studies are seldom of value in evaluation of CMV disease.
  • Exceptions include the rare patient with severe mononucleosis caused by primary CMV infection who may require abdominal ultrasound for monitoring of splenomegaly or the immunocompromised patient who requires chest radiograph studies for the possibility of CMV pneumonitis.

Other Tests

• Other tests are indicated, based on the organ systems involved and manifestations of disease syndromes.

Procedures

• Procedures depend on the age of the patient and manifestations of disease syndromes.
  • For infants, procedures may include lumbar puncture or liver biopsy.
  • For immunocompromised transplant recipients, bronchoalveolar lavage, tissue or organ biopsy, and lumbar puncture may all be required to evaluate for extent of CMV-associated disease.
• For some patients with AIDS who have retinitis, placement of ganciclovir-impregnated intravitreal implants may be an important ancillary procedure.

Histologic Findings

• The classic tissue histological finding in cytomegalic disease is the inclusion cell; however, viral culture, serology, antigenemia, and nucleic acid detection systems (eg, PCR) generally have much better sensitivity for the diagnosis of CMV-associated diseases.

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