Cytomegalovirus infection and disease reduce 10-year cardiac allograft vasculopathy-free survival in heart transplant recipients

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Abstract

Background

Cytomegalovirus (CMV) is associated with an increased risk of cardiac allograft vasculopathy (CAV), the major limiting factor for long-term survival after heart transplantation (HTx). The purpose of this study was to evaluate the impact of CMV infection during long-term follow-up after HTx.

Methods

A retrospective, single-centre study analyzed 226 HTx recipients (mean age 45 ± 13 years, 78 % men) who underwent transplantation between January 1988 and December 2000. The incidence and risk factors for CMV infection during the first year after transplantation were studied. Risk factors for CAV were included in an analyses of CAV-free survival within 10 years post-transplant. The effect of CMV infection on the grade of CAV was analyzed.

Results

Survival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0–7.4) compared with CMV disease (4.2 years; CI, 3.2–5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3–6.4; p = 0.013). In univariate analysis, recipient age, donor age, coronary artery disease (CAD), asymptomatic CMV infection and CMV disease were significantly associated with CAV-free survival. In multivariate regression analysis, CMV disease, asymptomatic CMV infection, CAD and donor age remained independent predictors of CAV-free survival at 10 years post-transplant.

Conclusions

CAV-free survival was significantly reduced in patients with CMV disease and asymptomatic CMV infection compared to patients without CMV infection. These findings highlight the importance of close monitoring of CMV viral load and appropriate therapeutic strategies for preventing asymptomatic CMV infection.

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Most cited references 29

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Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.

Susan Stewart, Gayle Winters, Michael Fishbein … (2005)

In 1990, an international grading system for cardiac allograft biopsies was adopted by the International Society for Heart Transplantation. This system has served the heart transplant community well, facilitating communication between transplant centers, especially with regard to patient management and research. In 2004, under the direction of the International Society for Heart and Lung Transplantation (ISHLT), a multidisciplinary review of the cardiac biopsy grading system was undertaken to address challenges and inconsistencies in its use and to address recent advances in the knowledge of antibody-mediated rejection. This article summarizes the revised consensus classification for cardiac allograft rejection. In brief, the revised (R) categories of cellular rejection are as follows: Grade 0 R--no rejection (no change from 1990); Grade 1 R--mild rejection (1990 Grades 1A, 1B and 2); Grade 2 R--moderate rejection (1990 Grade 3A); and Grade 3 R--severe rejection (1990 Grades 3B and 4). Because the histologic sub-types of Quilty A and Quilty B have never been shown to have clinical significance, the "A" and "B" designations have been eliminated. Recommendations are also made for the histologic recognition and immunohistologic investigation of acute antibody-mediated rejection (AMR) with the expectation that greater standardization of the assessment of this controversial entity will clarify its clinical significance. Technical considerations in biopsy processing are also addressed. This consensus revision of the Working Formulation was approved by the ISHLT Board of Directors in December 2004.

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Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival.

Solbjørg Sagedal, Anders Hartmann, Knut P Nordal … (2004)

The impact of cytomegalovirus (CMV) infection and disease on long-term outcome after kidney transplantation is still unsettled. Between 1994 and 1997, 397 consecutive first kidney graft recipients and 74 retransplants were included in the study and followed prospectively until December 31, 2001. CMV infection (CMV pp65 antigenemia) and CMV disease were recorded once weekly during the first 100 days after transplantation. No CMV prophylaxis or preemptive therapy was given. In a multiple Cox proportional hazard model allowing time-dependent covariates, the effects of asymptomatic CMV infection and CMV disease, recipient age and gender, retransplantation, living donor, panel-reactive cytotoxid antibodies, acute rejection, and graft loss were tested on overall mortality beyond 100 days post-transplantation. In a similar analysis, the effect of asymptomatic CMV infection and CMV disease plus other factors were tested on death censored graft loss beyond 100 days. Median (range) follow up time was 66.6 (<1-86.9) months. The incidence of CMV infection and disease during the first 100 days was 62.8% and 23.4%, respectively. The number of total deaths was 96 (20%), 82 occurred after the first 100 days. Independent risk factors for overall mortality beyond 100 days were asymptomatic CMV infection, RR = 2.90 (95% CI 1.61-5.22) (P= 0.001), CMV disease, RR = 2.50 (95% CI 1.31-4.79) (P= 0.006), both compared to no infection or disease, recipient age, RR = 1.066 per year (95% CI 1.048-1.084) (P < 0.001), and graft loss in the whole study period RR = 7.88 (95% CI 4.75-13.08) (P < 0.001). Asymptomatic CMV infection and CMV disease were not independent risk factors for death censored graft loss, but they significantly reduced graft survival uncensored for death, (log rank P= 0.001, respectively). Asymptomatic CMV infection and overt CMV disease during the first 100 days increase the risk of recipient mortality beyond 100 days. This raises the question whether CMV prophylaxis should be given routinely after kidney transplantation.

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Cardiac allograft vasculopathy after heart transplantation: risk factors and management.

Hannah Valantine (2004)

Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors-smoking, obesity, diabetes, dyslipidemia and hypertension-are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of ischemic heart disease, cerebrovascular disease and peripheral vascular disease. The choice of calcineurin inhibitor for an immunosuppressive regimen in heart transplantation should consider the associated relative cardiovascular risks.

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Author and article information

Contributors

Inger Johansson: inger.johansson@infect.gu.se

Rune Andersson: rune.andersson@gu.se

Vanda Friman: vanda.friman@gu.se

Nedim Selimovic: nselimovic@kfshrc.edu.sa

Lars Hanzen: lars.hanzen@liv.se

Salmir Nasic: salmir.nasic@vgregion.se

Ulla Nyström: ulla.m.nystrom@vgregion.se

Vilborg Sigurdardottir: vilborg.sigurdardottir@insel.ch

Journal

Journal ID (nlm-ta): BMC Infect Dis

Journal ID (iso-abbrev): BMC Infect. Dis

Title: BMC Infectious Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2334

Publication date (Electronic): 24 December 2015

Publication date PMC-release: 24 December 2015

Publication date Collection: 2015

Volume: 15

Electronic Location Identifier: 582

Affiliations

[ ]Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

[ ]Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden

[ ]Research and Development Centre, Skaraborg Hospital, Skövde, Sweden

[ ]Department of Cardiology, Swiss Cardiovascular Centre, University Hospital (Inselspital Bern) and University of Bern, Bern, Switzerland

Article

Publisher ID: 1321

DOI: 10.1186/s12879-015-1321-1

PMC ID: 4690411

PubMed ID: 26703239

SO-VID: 5bdb5d9e-28e9-492e-aa0c-3343a2aa2b73

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.