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Detection and quantification of cytomegalovirus (CMV) viremia
Monitoring CMV disease progression and response to antiviral therapy
Cytomegalovirus (CMV) is a common and major cause of opportunistic infection in organ transplant recipients, causing significant morbidity and mortality. CMV infection and disease typically occur during the first year after organ transplantation after cessation of antiviral prophylaxis. Such infection usually manifests as fever, leukopenia, hepatitis, colitis, or retinitis. Other manifestations of CMV infection in this population may be more subtle and include allograft injury and loss, increased susceptibility to infections with other organisms, and decreased patient survival (ie, indirect effects). The risk of CMV disease is highest among organ recipients who are CMV seronegative prior to transplantation and receive allografts from CMV-seropositive donors (ie, CMV D+/R- mismatch). The infection is transmitted via latent CMV present in the transplanted organ donor and the virus subsequently reactivates, causing a primary CMV infection in the recipient. CMV disease may also occur from reactivation of the virus already present within the recipients. Factors, such as the type of organ transplanted, intensity of the antirejection immunosuppressive therapy, advanced age, and presence of comorbidities in the recipient, are also associated with increased risk for CMV disease after allograft transplantation. Lung, heart, small intestine, pancreas, and kidney-pancreas transplant recipients are at greater risk for CMV infection than kidney and liver transplant recipients.
Among the various clinical laboratory diagnostic tests currently available to detect CMV infection, nucleic acid amplification tests (eg, PCR) are the most sensitive and specific detection methods. In addition, quantification of CMV DNA level in peripheral blood (ie, CMV viral load) is used routinely to determine when to initiate preemptive antiviral therapy, diagnose active CMV disease, and monitor response to antiviral therapy. A number of factors can affect CMV viral load results, including the specimen type (whole blood versus plasma), biologic properties of CMV, performance characteristics of the quantitative assay (eg, limit of detection, limits of quantification, linearity, and reproducibility), degree of immunosuppression, and intensity of antiviral therapy.
In general, higher CMV viral loads are associated with tissue-invasive disease, while lower levels are associated with asymptomatic infection. However, the viral load in the peripheral blood compartment may be low or not detectable in some cases of tissue invasive disease. Since wide degree of overlap exists in CMV viral load and disease, rise in viral load over time is more important in predicting CMV disease than a single viral load result at a given time point. Therefore, serial monitoring (eg, weekly intervals) of organ transplant recipients with quantitative CMV PCR is recommended in such patients at risk for CMV disease. Since changes in viral load may be delayed by several days in response to antiviral therapy and immunosuppression, viral load should not be monitored more frequently than a weekly basis. Typically, CMV viral load changes of >0.5 log IU/mL are considered biologically significant changes in viral replication. Patients with suppression of CMV replication (ie, viral load of <137 or <2.1 log IU/mL at days 7, 14, and 21 of treatment) had shorter times to resolution of clinical disease than those without viral suppression. No degree of relative viral load reduction from pretreatment level was associated with faster resolution of CMV disease.
The quantification range of this assay is 137 to 9,100,000 IU/mL (2.14 log to 6.96 log IU/mL), with a > or =95% limit of detection at 91 IU/mL (1.96 log IU/mL).
A result of "Undetected" indicates the absence of cytomegalovirus (CMV) DNA in the plasma (see Cautions below).
A result of "Detected, but <137 IU/mL (<2.14 log IU/mL)" indicates that CMV DNA is detected in the plasma, but the assay cannot accurately quantify the CMV DNA present below this level.
A quantitative value (reported in IU/mL and log IU/mL) indicates the level of CMV DNA (ie, viral load) present in the plasma.
A result of "Detected, but >9,100,000 IU/mL (>6.96 log IU/mL)" indicates that CMV DNA level present in plasma is above 9,100,000 IU/mL (6.96 log IU/mL), and the assay cannot accurately quantify CMV DNA present above this level
Cytomegalovirus (CMV) DNA level in plasma should not be used as the only criterion used in the diagnosis and therapeutic decision for CMV disease. Viral load should be correlated with other laboratory test results and clinical presentation. The trend of viral load over time is more useful than a single absolute value for predicting the presence of CMV disease.
A result of "Undetected" does not necessarily indicate the absence of CMV infection, since low-level viral replication may be below the limit of detection of the assay. False-negative or falsely low viral load results can be caused by improper specimen collection or storage prior to testing.
Some patients with tissue-invasive CMV disease may not have detectable viral load in the peripheral blood. In such cases, CMV-specific immunohistochemical stains and qualitative detection of CMV DNA from tissue biopsy would provide useful and definitive evidence of CMV disease.
This assay should be used only to test plasma from at-risk patients with a clinical history and symptoms and signs suggestive with CMV infection; viral load results must be interpreted in the context of the clinical picture. This test is not indicated for screening asymptomatic patients without risk factors for CMV disease.
1. Kotton CN, Kumar D, Caliendo A, et al: International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010;89(7):779-795
2. Kraft CS, Armstrong WS, Caliendo AM: Interpreting quantitative cytomegalovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis 2012;54(12):1793-1797
3. Razonable RR, Asberg A, Rollag H, et al: Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard is predictive of CMV disease resolution in transplant recipients Clin Infect Dis 2013 Jun;56(11):1546-1553