VIENNA – Testing for an RNA biomarker of cytomegalovirus (CMV) infection rather than using well-established viral DNA assays may enable better therapeutic management of the infection in immunocompromised patients, according to a presentation at the European Society of Clinical Microbiology and Infectious Diseases global congress held here this week.
In a congress symposium on Saturday organized by Bruker, Carlo Federico Perno, director of clinical microbiology, immunology, and laboratory medicine at Bambino Gesù Children's Hospital in Rome, discussed recently published research on the new RNA biomarker, calling it a "game changer" for monitoring active viral infection and therapy efficacy in immunocompromised patients, particularly organ transplant recipients.
The establishment of this biomarker points to increased uptake of the CMV RNA Elite MGB kit, which was launched last year in the EU with CE-IVDR marking by EliTechGroup, which was acquired by Bruker earlier in 2024. It is the only commercial assay for the detection and quantitation of the biomarker, CMV RNA UL21.5.
CMV, a DNA herpesvirus, is an extremely common infection in the general population, with half of all people having an infection by age 40 and up to 90 percent of people having an infection by age 80.
Most people experience mild or no symptoms from infection, but people who are taking immune-suppressing medications for an organ or stem cell transplant are at elevated risk for serious complications from the virus, including pneumonia, retinitis, gastritis, encephalitis, or even death. The virus is also problematic for children under the age of 5 and individuals living with HIV.
The virus infects different tissue and cell types and can establish lifelong latent infection in its host. But whenever a patient is immunocompromised, the virus can begin an active infection and is the major burden of disease in solid organ and bone marrow transplant patients, which comprise about 80 percent of all patients at Bambino Gesù Children's Hospital, Perno said.
There are two types of post-transplant therapeutic management of CMV infection in these patients: prophylactic, in which an antiviral drug is given from time of transplant for a fixed period; and preemptive therapy (PET), in which CMV DNA levels (DNAemia) are monitored, and antiviral therapy is administered until CMV DNA is no longer detected.
In either case, a reliable indicator of active CMV infection is needed, and the gold standard for this has been DNA-based PCR testing. However, "DNAemia is really a surrogate marker of viral activity," Perno said. The presence of viral DNA in plasma can be due to abortive infection, which is clinically nonsignificant, or host cell death due to CMV DNA accumulation that does not lead to the production of viral particles during antiviral treatment, particularly with the gold standard prophylactic treatment, Merck's Prevymis (letermovir) — although other promising antivirals in the pipeline exploit a similar viral target as Prevymis and might cause the same issue.
As such, "we need to rethink our diagnostic procedure," Perno said.
He highlighted a research letter published last year in the journal Virology by investigators at the University of Bologna that established CMV RNAemia as a new marker of active viral replication in transplant recipients. It turns out that CMV, though a double-stranded DNA virus, also contains four species of RNA in its virion particles and that the CMV RNA UL21.5 biomarker is highly expressed during lytic infection. The biomarker is also located inside virions in the blood plasma, which is indicative of an active infection.
These researchers showed that taking CMV RNAemia into account alongside DNAemia provides more accurate information on viral load kinetics during post-transplant monitoring of infection, especially in patients receiving Prevymis. Importantly, CMV RNA PCR testing using the EliTech assay resulted in 100 percent diagnostic specificity, meaning that it didn't result in any false positives that might spur the unnecessary administration or continuation of antiviral drugs.
They also underscored that the new availability of a user-friendly assay on an automated and integrated molecular diagnostics system is a boon for patient management, as many of the steps involved with measuring DNAemia are laborious or prone to inaccuracy.
EliTech's test is patented, and is a one-step real-time reverse-transcription qPCR assay that runs exclusively on the company's two main molecular diagnostic platforms: the Elite InGenius and newer, higher-throughput Elite BeGenius system, both of which are also CE-IVDR marked.
According to an EliTech spokesperson, several other studies are in the works or have since been published regarding RNAemia testing for CMV infection, and multiple laboratories across Europe are now testing the assay. The spokesperson also noted that the assay could become a new gold standard as new antiviral drugs for CMV are introduced.
One notable new study by researchers at hospital group ASST Papa Giovanni XXIII in Bergamo, Italy, shows proof of concept that measuring CMV RNA can accurately predict the need for PET in children undergoing liver transplant. This study has been accepted for publication in the Journal of Medical Virology but is currently available online as a preprint.
Important findings from this study include the fact that CMV RNAemia was detectable in patients who would meet criteria for preemptive therapy, that CMV RNA appeared simultaneously to or even earlier than CMV DNA, that RNA levels peak with DNA, and that RNA clearance occurred earlier than DNA clearance.
Perno concluded at the ESCMID congress that CMV RNA positivity truly indicates potentially graft- and life-threatening infections that need to be promptly tackled, and that the high accuracy of the CMV RNA UL21.5 biomarker in predicting the need for PET suggest that using it to initiate antivirals in pediatric transplant patients could lead to "a timely intervention with no risk of overtreatment."