Ask the Experts - Positive CMV-Antigenemia With or Without PCR...
Some renal transplanted patients exhibit a positive cytomegalovirus (CMV)-antigenemia (more than 5 cells) with or without CMV-polymerase chain reaction (PCR) positive results and without any clinical signs of CMV infection. This combination was observed in several patients a few days after completing full treatment with oral ganciclovir (100 days at 3 g/day). What is your opinion about managing these patients? Must they receive another course of ganciclovir (intravenous or oral), or can they be monitored without any treatment as long as they do not develop active disease or a deterioration of kidney function?

There are currently 2 schools of thought regarding CMV disease prophylaxis in transplant recipients. Some centers use antiviral prophylaxis in at-risk patients for an established time period (usually 3 months) and then assay the patients for signs of CMV disease, while others follow assays closely during the postoperative period and treat "preemptively" when their patient's test becomes positive. It appears as though you follow the first approach and are experiencing the difficulties of the latter. Let me describe the shortcomings of the tests and then offer my opinion.

The CMV "antigenemia" assay assesses the number of peripheral blood lymphocytes (PBL) per 50,000 that are expressing the pp65 (65 kilodalton) protein. This antigen is expressed on the cell surface of infected cells, both before and during active viral replication, and has been identified as a significant antigenic target for cytotoxic T lymphocytes (CTLs). Such CMV-specific CTLs may be responsible for keeping viral load in check via the destruction of infected cells expressing the pp65 antigen. If the CMV-specific CTL response is intact, then some number of cells (usually < 10 per 50,000) may be present without clinical significance. If > 10 of 50,000 PBL stain positive for pp65, then the positive predictive value for the presence of CMV disease is reported to approach 100%.

Another set of assays based on the PCR appear to hold great promise for improving the sensitivity and specificity by which we diagnose CMV disease. There are 2 classifications of PCR for CMV: qualitative and quantitative assays. Qualitative PCR may only determine the presence (or absence) of CMV virus, but quantitative PCR can demonstrate the number of CMV DNA copies (viral load) -- that correlate with viral replicationand predate the onset of CMV disease. However, precise standardization of this test and correlation with objective clinical parameters of disease remain to be established. For example, > 100,000 viral copies per 10 leukocytes has been touted as indicative of impending or present CMV disease, while other investigators have reported results as the number of copies per milliliter of solution. Clearly, methods and reporting must be standardized before quantitative PCR can be widely applied clinically. According to one study, surveillance qualitative PCR had a positive predictive value for CMV disease of only 55%; conversely, there was a 100% negative predictive value. In short, PCR alone may be too sensitive in that it detects the presence of viral DNA and not necessarily the presence of disease. The presence of signs and symptoms is the key.

Most patients who develop symptomatic CMV infection exhibit mild symptoms consisting of fever, myalgia, malaise, lethargy, and mild dyspnea, often accompanied by leukopenia. Although increasingly uncommon, more serious manifestations include pneumonitis or pneumonia, gastrointestinal bleeding, nephritis, hepatitis, pancreatitis, and severe leukopenia, any of which can occur alone or in combination. If these signs and/or symptoms were present in your patient, then I would treat with intravenous ganciclovir for 2 or more weeks. If not, I would just follow the trends of your assays and check in frequently with the patient. Remember, CMV disease is manifest when the patient is over-immunosuppressed. Therefore, the other approach is to minimize the immunosuppression in any patient trending upwards in quantitative antigenemia or PCR. This will give ample opportunity for your patient's CMV-specific CTLs to do what needs to be done.