Viral endomyocardial infection is an independent predictor and potentially treatable risk factor for graft loss and coronary vasculopathy in pediatric cardiac transplant recipients

Abstract

Objectives: This study sought to evaluate the outcome and prevalence of viral endomyocardial infection after cardiac transplantation.

Background: Viral myocardial infection causes heart failure, but its role after cardiac transplantation is unclear. We hypothesized that viral infection of the cardiac allograft reduces graft survival.

Methods: Between June 1999 and November 2004, 94 pediatric cardiac transplant patients were screened for the presence of viral genome in serial endomyocardial biopsies (EMBs) using polymerase chain reaction (PCR) assays. Graft loss, advanced transplant coronary artery disease (TCAD), and acute rejection (AR) were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan-Meier and Cox regression analyses. From November 2002 to November 2004, intravenous immunoglobulin therapy (IVIG) was administered to patients with PCR-positive EMBs. The outcomes of the IVIG-treated, PCR-positive patients (n = 20) were compared with IVIG-untreated, PCR-positive patients (n = 17).

Results: Viral genomes were detected in EMBs from 37 (39%) patients; parvovirus B19, adenovirus, and Epstein-Barr virus (EBV) were the most common. The PCR-positive group (n = 37, 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57, 25% graft loss at 8.7 years) and developed advanced TCAD prematurely (p = 0.001). The number of AR episodes was similar in both groups. On multivariate analysis, presence of viral genome was an independent risk factor for graft loss (relative risk: 4.2, p = 0.015). The time to advanced TCAD after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend toward improved graft survival (p = 0.06).

Conclusions: Viral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients. This effect appears to be mediated through premature development of advanced TCAD. IVIG therapy in this subgroup may improve survival and merits further investigation.

Fig. 1. Overview of study design with patient selection, follow-up and analysis

Fig. 2. Prevalence and outcome of viral endomyocardial infection in a pediatric cardiac transplant cohort

A: Pie-chart showing the viral subtypes of the PCR-positive viral endomyocardial infections identified; Parvovirus B19, adenovirus and EBV were most commonly identified. B: Bar-graph showing a changing trend in the viral composition of PCR-positive viral endomyocardial infection during the study period from 1999–2004 with a surge in Parvovirus B19 in 2003 and 2004 and a concomitant decrease in adenoviral infections. C: Kaplan-Meier curve for freedom from viral endomyocardial infection after cardiac transplantation shows that the first year post-transplantation is the highest risk period. D: Kaplan-Meier curves for graft survival show that graft survival is worse in the viral PCR-positive patients compared to the viral PCR-negative patients (p<0.001, logrank). E: Kaplan-Meier curves for freedom from advanced TCAD show that the viral PCR-positive patients develop advanced TCAD prematurely compared to the PCR-negative group (p=0.001, logrank). F: Predicted survival curves for individual viruses after Cox regression show that patients with adenoviral and EBV endomyocardial infection have a worse outcome compared to PCR-negative or CMV-positive or Parvo-positive patients.

Fig. 3. Kaplan-Meier analysis of the utility of IVIG-therapy in pediatric cardiac transplant patients with viral endomyocardial infection

3A: Overall graft survival tends to be worse in the PCR-positive IVIG-untreated subgroup compared to PCR-positive IVIG-treated patients or PCR-negative patients 3B: Graft survival after developing viral endomyocardial infection tends to be better in the IVIG-treated patients compared to the IVIG-untreated controls (p=0.06, logrank). 3C: PCR-positive IVIG-untreated patients have an earlier overall onset of advanced TCAD compared to PCR-positive IVIG-treated patients. 3D: IVIG therapy in patients with viral endomyocardial infection delays the time to onset of advanced TCAD from the first PCR-positive biopsy (p=0.03, logrank).