Detection of Epstein–Barr virus DNA in peripheral blood is associated with the development of bronchiolitis obliterans syndrome after lung transplantation

https://doi.org/10.1016/j.jcv.2009.02.005Get rights and content

Abstract

Background

The long-term success of lung transplantation is limited by the development of bronchiolitis obliterans syndrome (BOS). Virus infections may be involved in the development of BOS.

Objectives

The study intended to investigate whether there is an association of Epstein–Barr virus (EBV), cytomegalovirus (CMV) and human adenovirus (HAdV) with the development of BOS and to identify risk factors for EBV detection in blood.

Study design

A prospective cohort study was conducted in lung and heart–lung transplant recipients (LTR) who are followed in our outpatient clinic. 385 LTR were monitored for CMV pp65 antigen, EBV and HAdV DNA in blood at follow-up visits for 6 months. The development of BOS was recorded for a median of 21 months.

Results

EBV DNA, HAdV DNA and CMV pp65 antigen were detected at least once in, respectively, 202/385 LTR (52.5%), 10/382 LTR (2.6%) and 19/385 LTR (4.9%).

Repeated EBV DNA detection and acute rejection were associated with the development of BOS. Variables associated with EBV DNA detection in blood were the diagnosis of BOS before study entry, retransplantation and immunosuppressive therapy with sirolimus or everolimus.

Conclusions

EBV reactivation is frequent in LTR. The variables found associated with EBV reactivation probably reflect increased immunosuppression. Repeated EBV DNA detection in blood, possibly reflecting chronic EBV replication, is associated with the development of BOS. The elucidation of whether and how EBV DNAemia triggers the development of BOS could improve long-term survival of LTR.

Section snippets

Background

Lung transplantation is a therapy for end-stage lung disease. However, lung transplantation is complicated by chronic organ dysfunction termed bronchiolitis obliterans syndrome (BOS) (according to clinical criteria) which develops in about 50% of LTR until 5 years after transplantation. It is the most important risk factor for five-year mortality.1 Repeated acute rejection is a risk factor for BOS and several studies suggest that cytomegalovirus (CMV) and respiratory virus infections play a

Study design

A prospective cohort study was performed in lung and heart–lung transplant recipients (called LTR) transplanted between 1988 and 2006 who were followed up in the outpatient clinic of Medizinische Hochschule Hannover. Inclusion criteria: adult LTR; informed consent to participate in the study; at least one outpatient clinic visit during the study period (October 31, 2005 to April 28, 2006). 16 LTR who refused consent and three who had no blood specimen examined for EBV DNA were excluded (Fig. 1

Results

385 LTR were included and visited the outpatient clinics 769 times during the study period (6 months; median one visit per patient, range 1–9). Patient demographics are shown in Table 1.

86 LTR (22.3%) had been diagnosed with BOS before study entry. Seven LTR were first diagnosed with BOS at the time of the study visit. 38 (13.0%) of the remaining 292 LTR developed BOS after inclusion in the study. 5 LTR received a retransplantation. 31 LTR died during the follow-up period of whom 22 had EBV DNA

Discussion

This is so far the largest cohort of LTR studied to address the question whether EBV, CMV and HAdV contribute to the development of BOS. EBV DNA, HAdV DNA and CMV pp65 antigen were detected in the blood of, respectively, 52.5%, 2.6% and 4.9% of LTR at least once. The frequency of EBV DNA detection was comparable to that found in smaller cohorts of LTR.13, 14, 15 The frequency of CMV pp65 antigen and HAdV DNA detection was lower than reported by others16, 17 possibly due to different observation

Conflict of interest

None.

Ethical approval

The study was approved by the review board of Medizinische Hochschule Hannover.

Acknowledgements

The study was supported from core funding of Medizinische Hochschule Hannover. The excellent technical assistance of M. Wehrhane and S. Hübner is acknowledged. We thank M. Zühlsdorf, M. Dierich and N. Hesse for help with data acquisition.

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    The study was registered at www.clinicaltrials.gov with the number NCT00701922.

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