Characterization of Cytomegalovirus Disease in Solid Organ Transplant Recipients by Markers of Inflammation in Plasma Halvor Rollag 1,6 *, Thor Ueland 2,5 , Anders A ˚ sberg 3 , Anders Hartmann 4,6 , Alan G. Jardine 7 , Atul Humar 8 , Mark D. Pescovitz 9{ , Angelo A. Bignamini 10 , Pa ˚l Aukrust 2,4,5 1 Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, 2 Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway, 3 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway, 4 Department of Organ Transplantation, Gastroenterology and Nephrology, Section for Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, 5 Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway, 6 Faculty of Medicine, University of Oslo, Oslo, Norway, 7 Department of Medicine, University of Glasgow, Glasgow, United Kingdom, 8 Department of Medicine, University of Alberta, Edmonton, Canada, 9 Departments of Surgery and Microbiology/Immunology, Indiana University, Indianapolis, Indiana, United States of America, 10 School of Specialization in Hospital Pharmacy, University of Milan, Milan, Italy Abstract Background: While several studies have examined the general inflammatory responses in relation to cytomegalovirus infection, the identification of the various inflammatory mediators as well as their relative importance is far from clear. Patients and Methods: Solid organ recipients enrolled in an international multicenter trial of cytomegalovirus disease treatment (the VICTOR study) were analyzed (n = 289) (ClinicalTrials.gov NCT00431353). Plasma markers of inflammation and endothelial cell activation were assessed at baseline by enzyme immunoassays. Results: The major findings were: (i) Plasma levels of the CXC-chemokine interferon-inducible protein-10 (P,0.001) and C- reactive protein (P = 0.046) were independently associated with the presence of cytomegalovirus DNAemia above lower level of quantification. (ii) High levels of CC-chemokine ligand 21 (P = 0.027) and pentraxin 3 (P = 0.033) were independently associated with tissue invasive cytomegalovirus disease as opposed to cytomegalovirus syndrome. Conclusion: Our findings illustrate the complex interaction between cytomegalovirus and the immune system, involving a wide range of inflammatory mediators that could be associated to disease manifestations in cytomegalovirus related disease. Citation: Rollag H, Ueland T, A ˚ sberg A, Hartmann A, Jardine AG, et al. (2013) Characterization of Cytomegalovirus Disease in Solid Organ Transplant Recipients by Markers of Inflammation in Plasma. PLoS ONE 8(4): e60767. doi:10.1371/journal.pone.0060767 Editor: Martin Rowe, University of Birmingham, United Kingdom Received December 6, 2012; Accepted March 2, 2013; Published April 8, 2013 Copyright: ß 2013 Rollag et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have the following interests. Dr. A ˚ sberg is a former employee of F. Hoffmann-La Roche Ltd. (between 2000 and 2003) and served as a consultant to F. Hoffmann-La Roche Ltd during the study dealing with study specific issues. Drs. Humar, Jardine, Hartmann and Rollag have performed consultancy work for F. Hoffmann - La Roche Ltd. Drs Aukrust and Ueland have no conflicts of interest to report. Dr. Bignamini was employed by Hyperphar during the study, which was a sub-contractor for F.Hoffmann-La Roche Ltd, hired to perform data management and statistical analyses. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. * E-mail: halvor.rollag@rr-research.no { Deceased. Introduction Cytomegalovirus (CMV) is a major viral pathogen affecting solid organ transplant recipients, and is responsible for substantial morbidity in affected individuals. The clinical manifestations of CMV include an acute viral syndrome as well as tissue invasive diseases including pneumonitis, hepatitis and gastrointestinal disease [1]. In addition to these CMV-induced manifestations, CMV has immunomodulatory effects that predispose to opportu- nistic infections as well as acute and chronic allograft rejection in the infected host [1,2]. Cytokines and chemokines orchestrate the interaction between CMV and the immune system, as they participate in reactivation of latent virus and regulation of viral replication [3]. In addition to host-encoded cytokines and chemokines, the virus itself encodes homologues of these proteins and their receptors as an immune escape strategy [4,5]. The CMV-mediated inflammatory responses are also important determinants of tissue damage and clinical manifestations of CMV infection [6]. However, while several studies have examined the general inflammatory responses in relation to CMV infection, the identification of the specific inflammatory mediators and their relative importance in relation to pathogenesis of CMV disease is unclear. We have recently reported that pretreatment levels of inflam- matory markers were associated with virological and clinical outcomes in solid organ transplant recipients with CMV infection PLOS ONE | www.plosone.org 1 April 2013 | Volume 8 | Issue 4 | e60767