Original Clinical ScienceçGeneral The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation Camille N. Kotton, MD,1 Deepali Kumar, MD,2 Angela M. Caliendo, MD, PhD,3 Shirish Huprikar, MD,4 01/28/2019 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3pzrw1VmaZXQ+S1X5qzIxw8+AIlXMhR5CNF7trXzV+w4= by https://journals.lww.com/transplantjournal from Downloaded Sunwen Chou, MD,5 Lara Danziger-Isakov, MD, MPH,6 and Atul Humar, MD7 Downloaded on behalf of the The Transplantation Society International CMV Consensus Group from https://journals.lww.com/transplantjournal Abstract: Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized ap- proach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3pzrw1VmaZXQ+S1X5qzIxw8+AIlXMhR5CNF7trXzV+w4= of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immuno- suppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations. (Transplantation 2018;102: 900–931) he past 5 years has seen exciting advances related to the convened in 2008 and 2012 by The Infectious Diseases Sec- Tunderstanding, diagnosis, and treatment of Cytomega- tion of The Transplantation Society to develop consensus lovirus (CMV). We currently stand on the cusp of moderniz- guidelines on CMV management, subsequently published ing the management of CMV infection posttransplant. in 20104 and 2013.5 Topics included diagnostics, immunol- Despite these advances, CMV remains one of the most com- ogy, prevention, treatment, resistance, and pediatrics. Given mon complications affecting solid organ transplant recipients numerous recent advances in the field, a third meeting of ex- (SOTR), still befitting the designation: “a transplantation perts was convened in March 2017 to update these guidelines. troll.”1 In addition to the direct effects of CMV infection The expert panel rated the quality of evidence on which and disease, there are “indirect effects,” both general and recommendations are based by following a process used in transplant-specific, and higher rates of all types of infection, the development of other guidelines, including those by the graft loss, morbidity, and mortality.2,3 A panel of experts on Infectious Diseases Society of America. The Grading of Rec- CMV and solid organ transplantation (SOT) was previously ommendations Assessment, Development and Evaluation Received 15 January 2018. Revision received 12 March 2018. from Roche, Shire, Qiagen, Oxford Immunotec as well as consultancy fees from Accepted 13 March 2018. Qiagen and Oxford Immunotec. S.C. performed contracted CMV phenotyping on research for Merck and Shire. S.H. and L.D.-I. have no conflicts to declare. A.H. 1 01/28/2019 Transplant and Immunocompromised Host Infectious Diseases Infectious Dis- received research support from Qiagen, Astellas and Roche. eases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA. All authors participated in the consensus meeting, review and summary of available data, and in the writing of the article. 2 Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada. The CMV Consensus Conference was organized by the Infectious Diseases Section of The Transplantation Society. Independent, nonrestricted grants from Hoffman 3 Rhode Island Hospital, Providence, RI. LaRoche, Merck, Oxford Immunotec, Qiagen, Shire, CSL Behring, Lophius 4 Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Biosciences, Chimerix, Roche Molecular Systems, and Abbott Laboratories made 5 Division of Infectious Diseases, Oregon Health & Science University, Portland, OR. this conference possible. At no time did the funding sources have input into the list of attendees, discussion, or content. 6 Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. Correspondence: Camille N. Kotton, MD, Transplant and Immunocompromised Host Infectious Diseases Infectious Diseases Division, Massachusetts General 7 Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Hospital, Harvard Medical School 55 Fruit Street, Cox 5, Boston, MA 02114. Canada. ([email protected]). C.N.K. received funding for serving on scientific advisory boards for Roche Molecular Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. and Merck; adjudication boards for Astellas, Merck, and Shire; and consultancy fees from Qiagen and Oxford Immunotec. A.M.C. received funding for serving on a ISSN: 0041-1337/18/10206-0900 scientific advisory board for Roche Molecular. D.K. has received research grants DOI: 10.1097/TP.0000000000002191 900 www.transplantjournal.com Transplantation ■ June 2018 ■ Volume 102 ■ Number 6 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. © 2018 Wolters Kluwer Kotton et al 901 system allows for a systematic weighting of the strength of As in our prior versions, the term deoxyribonucleic acid recommendation (eg, “high, moderate, low, very low”)and in blood (DNAemia) will be used instead of viremia, to re- quality of evidence (eg, “strong, weak”)(Table1).6-10,13 flect the detection of CMV DNA in blood or plasma (whether We used the following definitions, consistent with the actively replicating virus or not). For accuracy, the phrases American Society of Transplantation and the CMV Drug Devel- “viral load” or “quantitative nucleic acid amplification opment Forum recommendations for use in clinical trials14,15: testing (QNAT)” are used instead of “polymerase chain reaction (PCR).” • CMV infection: evidence of CMV replication regardless of symptoms (differs from latent CMV); “defined as virus isola- tion or detection of viral proteins (antigens) or nucleic acid DIAGNOSTICS in any body fluid or tissue specimen”15 Pretransplant Testing • CMV disease: evidence of CMV infection with attributable symptoms. CMV disease can be further categorized as a viral Given that the CMV serostatus of donor and recipient syndrome (ie, fever, malaise, leukopenia, and/or thrombocy- (D/R) are key predictors of the risk of CMV after transplant topenia),orastissueinvasive(“end organ”) disease. and guide decisions on antiviral prophylaxis or preemptive TABLE 1. GRADE strength of recommendations and quality of the evidence6-12 Strength of recommendation Clarity of balance between desirable Methodological quality of supporting and quality of evidence and undesirable effects evidence (examples) Implications Strong recommendation, Desirable effects clearly outweigh Consistent evidence from well-performed Recommendation can apply to most patients high-quality evidence undesirable effects, or vice versa RCTs or exceptionally strong evidence in most circumstances. Further research is from unbiased observational studies unlikely to change our confidence in the estimate of effect Strong recommendation, Desirable effects clearly outweigh Evidence from RCTs with important Recommendation can apply to most patients moderate-quality undesirable effects, or vice versa limitations (inconsistent results, in most circumstances. Further research evidence methodological flaws, indirect, (if performed) is likely to have an important or imprecise) or exceptionally strong impact on our confidence in the estimate evidence from unbiased of effect and may change the estimate. observational studies Strong recommendation, Desirable effects clearly outweigh Evidence for at least 1 critical outcome Recommendation may change when low-quality evidence undesirable effects, or vice versa from observational studies, RCTs with higher-quality evidence becomes available. serious flaws or indirect evidence Further research (if performed) is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Strong recommendation Desirable effects clearly outweigh Evidence for at least 1 critical outcome Recommendation may change when very-low-quality evidence undesirable effects, or vice versa from unsystematic clinical observations higher-quality evidence becomes available; (very rarely applicable) any estimate of effect for at least 1 critical or very indirect evidence outcome is very uncertain. Weak recommendation, Desirable effects closely balanced Consistent evidence from well-performed The best action may differ depending on high-quality evidence with undesirable effects RCTs or exceptionally strong evidence circumstances or patients or societal values. from unbiased observational studies Further research is unlikely to change our confidence in the estimate of effect. Weak recommendation, Desirable effects closely balanced Evidence from RCTs with important Alternative approaches likely to