Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients

Abstract

Background: The rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.

Methods: Using stored serial serum specimens from renal (n = 59) and liver (n = 35) transplant recipients (D+R-; CMV-seropositive donors, CMV-seronegative recipients) from 2 prospective, randomized, controlled, interventional prophylaxis trials of CMV immune globulin (CMVIG), CMV viral load was measured using the COBAS quantitative polymerase chain reaction assay and the World Health Organization CMV standard. Patients with severe CMV-associated disease were classified according to trial definitions. Pairwise comparisons of mean viral load among deceased, surviving diseased, and nondiseased patients were analyzed by 2-way analysis of variance. To determine if viral load could predict mortality, receiver operating characteristic (ROC) curves were constructed using area under the curve (AUC) of the viral load and peak viral concentration (V_max).

Results: Viral load (mean log₁₀ [AUC], peak viral load [V_max]) for patients with severe CMV disease was significantly higher compared with nondiseased patients (P < .001). Similarly, higher viral burden was significantly associated with mortality (P < .001). Viral load AUC and V_max AUROCs for predicting mortality were 0.796 and 0.824, respectively, for renal patients, and 0.769 and 0.807, respectively, for liver patients.

Conclusions: Using specimens from studies preceding the antiviral prophylaxis era, CMV viral load was associated with severe CMV disease and death, supporting CMV viral load quantification as a proxy for CMV disease severity and disease-associated mortality end points in solid organ transplantation.

Keywords: cytomegalovirus; cytomegalovirus disease; liver transplantation; renal transplantation; viremia.

Figure 1.

Patient disease characteristics. ^aFour liver transplant patients were excluded from analyses due to insufficient sampling. One patient had no disease; of the 3 patients with severe disease, 1 patient died, and 1 patient was followed to day 15 and then received a new transplant. ^bOne liver transplant patient with mild disease was included in the severe disease category for analysis purposes. ^cThe total number of deaths was 10 (Table 1). One patient was excluded from death comparison analyses because cause of death was unrelated to cytomegalovirus (CMV).

Figure 2.

Cytomegalovirus (CMV) viral burden in (A) renal transplant patients and (B) liver transplant patients with or without CMV disease. Viral load areas under the curve (AUCs) and peak viral loads (V_max) were determined in subsets of patients with no disease, mild disease, or severe CMV disease and included CMV-associated disease. P values were calculated using the Tukey-Kramer test. Circles represent individual patients within each subset given CMV immune globulin (red) or placebo (black); boxes represent interquartile range; whiskers represent the upper and lower 25% of values; bold lines represent group median values; dashed lines represent group mean values.

Figure 3.

Association of cytomegalovirus (CMV) viral burden with disease or mortality in (A) renal transplant patients and (B) liver transplant patients. Areas under the curve (AUCs) and peak viral loads (V_max) were determined in subsets of patients who died as a result of severe CMV or CMV-associated disease (renal, n = 6; liver, n = 9) compared with survivors (renal, n = 53; liver, n = 25). Pairwise comparisons of AUC and V_max were performed using the Tukey-Kramer test. Black circles represent individual patients within each subset; boxes represent interquartile range; whiskers represent the upper and lower 25% of values; bold lines represent group median values; dashed lines represent group mean values.

Figure 4.

Receiver operating characteristic (ROC) curves for predicting mortality in renal and liver transplant patients using CMV viral load area under the curve (AUC) and peak viral load (V_max). Abbreviation: AUROC, area under the ROC curve.