Photo Credit: Ekaterina Chizhevskaya

A new report from a major CMV research and advocacy group describes changes to how specific CMV-related terms are defined in transplant recipients.

A major cytomegalovirus research and advocacy group has released an updated consensus paper in hopes of helping researchers in the field consistently report results of clinical trials, with significant changes to how certain cytomegalovirus (CMV)-related terms are defined in transplant recipients.

The consensus paper from the Transplant Associated Virus Infections Forum (formerly CMV Forum), published in Clinical Infectious Diseases, updates a 2017 consensus paper to account for new antiviral agents and other developments in CMV care.

In an editorial accompanying the paper, Jennifer M. Cuellar-Rodriguez, MD, director of the Transplant Infectious Diseases Consult Service at the National Institute of Allergy and Infectious Disease, Bethesda, Maryland, and David van Duin, MD, PhD, director of the Immunocompromised Host Infectious Diseases Section in the department of medicine at University of North Carolina School of Medicine, Chapel Hill, outlined the most significant changes. The authors noted that the updates were “not explicitly recommended for managing patients in daily clinical practice, although this is a common result of such consensus documents.”

“With scientific advances, the diagnostic approaches to CMV disease have evolved,” Dr. Cuellar-Rodriguez and Dr. van Duin explained in their editorial. “Given the wide availability of peripheral blood molecular diagnostics for the detection of CMV DNAemia, it is sometimes perceived by bedside physicians that the risk of undergoing tissue diagnosis is not justified when a compatible clinical syndrome is already present and the need to start a specific antiviral therapy accepted otherwise. This practice, however, can make enrolling patients in clinical trials significantly more difficult. This is particularly true for conventional diagnostics for CMV end-organ disease, in which tissue biopsies of the affected organ remain the reference standard but may impose additional risk in certain scenarios.”

Significant Updates to CMV Consensus Paper

The first update the commentators addressed was that the new paper recognizes that CMV disease may manifest differently in various transplants. This change means that researchers can include different, well-defined populations for enrollment in large clinical trials, with CMV pneumonia and CMV colitis as two examples.

Another important update to the paper is adding the term “clinically significant CMV infection” to the group’s list of definitions. This term was first used in studies of prophylactic letermovir in hematopoietic cell transplantation (HCT) and has since become common in certain medical circles.

The new updates also consolidate two previously distinct categories: “refractory” and “probable refractory” disease, once two separate categories, are now one. 

A Cutoff for CMV Disease?

Dr. Cuellar-Rodriguez and Dr. van Duin wrote that one update addressed “an area of controversy.” The group consensus paper suggests a “specific threshold in quantitative polymerase chain reaction testing of bronchoalveolar lavage (BAL) fluid in HCT recipients,” the commenters explained. “Studies of the utility of CMV Nucleic Acid Testing (NAT) testing in BAL fluid, particularly those that used quantitative PCR, all agree that a negative or very low quantitative PCR result in BAL fluid has a high negative predictive value for CMV pneumonia. However, they wrote that it has proven challenging to establish a cutoff for what constitutes CMV disease.

The forum authors suggested that among patients who present with a compatible syndrome and show no evidence of co-pathogens, a quantitative PCR cutoff of CMV DNA level of at least 3.0 log10 IU/mL indicated “relevant CMV replication.”

“It should be noted that this proposed cutoff has not been validated prospectively; some studies do support this threshold, but data from other studies suggest different cutoffs even in a similar population of patients,” Dr. Cuellar-Rodriguez and Dr. van Duin wrote. “The inclusion of this cutoff will certainly encourage research to validate or disprove the appropriateness of such a cutoff, ideally through multicenter studies, with protocolized processing of BAL fluid and fully automated assays for CMV DNA quantification.” 

More Updates to Come

“Overall, this new update will continue to shape the design of clinical trials among different transplant recipients at risk of CMV disease and allow for cross-trial comparison and advancement of CMV diagnostics and antivirals,” Dr. Cuellar-Rodriguez and Dr. van Duin concluded. “It also illustrates the urgent need to continue to perform collaborative research in the CMV diagnostic arena. Periodic revisions may be needed as difficulties in implementation or interpretation are encountered and new diagnostics become available.”