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Kotton CN, Kumar D, Manuel O, Chou S, Hayden RT, Danziger-Isakov L, Asberg A, Tedesco-Silva H, Humar A. The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation 2025:00007890-990000000-01056. [PMID: 40200403 DOI: 10.1097/tp.0000000000005374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Affiliation(s)
- Camille N Kotton
- Transplant and Immunocompromised Host Service, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Deepali Kumar
- Division of Infectious Diseases, Department of Medicine, Ajmera Transplant Center and University of Toronto, Toronto, ON, Canada
| | - Oriol Manuel
- Infectious Diseases Service and Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
| | - Sunwen Chou
- Division of Infectious Diseases, Oregon Health and Science University, Portland, OR
| | - Randall T Hayden
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
| | - Lara Danziger-Isakov
- Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Anders Asberg
- Department of Transplantation Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway
| | | | - Atul Humar
- Division of Infectious Diseases, Department of Medicine, Ajmera Transplant Center and University of Toronto, Toronto, ON, Canada
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Vo HD, Mackie F, McCulloch M, Reding R. International pediatric transplant association (IPTA) guidance on developing and/or expanding pediatric solid organ transplantation programs in low- and middle-income countries. Pediatr Transplant 2024; 28:e14346. [PMID: 36468319 DOI: 10.1111/petr.14346] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 06/11/2022] [Indexed: 12/11/2022]
Abstract
Pediatric solid organ transplantation (SOT) is a preferred treatment for medically suitable children with end-stage organ failure. Still, many of them have no access to transplantation owing to socioeconomic constraints or lack of transplant facilities in low- and middle-income countries (LMIC). Establishing pediatric SOT programs in LMIC offers children the opportunities to receive transplant care in more familiar home environments as well as help curtail transplant tourism and improve transplant outcomes as pediatric transplantation would be performed ethically and legally. The International Pediatric Transplant Association (IPTA) is a professional organization aiming to promote safe, ethical, and high-quality pediatric transplantation worldwide. This society paper describes major obstacles to pediatric SOT in LMIC and provides guidance on developing and/or expanding pediatric SOT programs in such countries. We also summarize available resources from the IPTA Outreach Program to help establish and support pediatric SOT programs in LMIC.
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Affiliation(s)
- Hanh D Vo
- Pediatric Gastroenterology, Hepatology, and Nutrition, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Fiona Mackie
- Paediatric Nephrology, Sydney Children's Hospital Randwick, University of New South Wales, Sydney, New South Wales, Australia
| | - Mignon McCulloch
- Pediatric Renal and Solid Organ Transplant Unit, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa
| | - Raymond Reding
- Pediatric Liver Transplant Program, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
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3
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Rabbani N, Kronmal RA, Wagner T, Kemna M, Albers EL, Hong B, Friedland-Little J, Spencer K, Law YM. Association Between Cytomegalovirus Serostatus, Antiviral Therapy, and Allograft Survival in Pediatric Heart Transplantation. Transpl Int 2022; 35:10121. [PMID: 35368645 PMCID: PMC8964945 DOI: 10.3389/ti.2022.10121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/10/2022] [Indexed: 11/30/2022]
Abstract
Background: Cytomegalovirus (CMV) is an important complication of heart transplantation and has been associated with graft loss in adults. The data in pediatric transplantation, however, is limited and conflicting. We conducted a large-scale cohort study to better characterize the relationship between CMV serostatus, CMV antiviral use, and graft survival in pediatric heart transplantation. Methods: 4,968 pediatric recipients of solitary heart transplants from the Scientific Registry of Transplant Recipients were stratified into three groups based on donor or recipient seropositivity and antiviral use: CMV seronegative (CMV-) transplants, CMV seropositive (CMV+) transplants without antiviral therapy, and CMV+ transplants with antiviral therapy. The primary endpoint was retransplantation or death. Results: CMV+ transplants without antiviral therapy experienced worse graft survival than CMV+ transplants with antiviral therapy (10-year: 57 vs 65%). CMV+ transplants with antiviral therapy experienced similar survival as CMV- transplants. Compared to CMV seronegativity, CMV seropositivity without antiviral therapy had a hazard ratio of 1.21 (1.07–1.37 95% CI, p-value = .003). Amongst CMV+ transplants, antiviral therapy had a hazard ratio of .82 (0.74–.92 95% CI, p-value < .001). During the first year after transplantation, these hazard ratios were 1.32 (1.06–1.64 95% CI, p-value .014) and .59 (.48–.73 95% CI, p-value < .001), respectively. Conclusions: CMV seropositivity is associated with an increased risk of graft loss in pediatric heart transplant recipients, which occurs early after transplantation and may be mitigated by antiviral therapy.
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Affiliation(s)
- Naveed Rabbani
- Division of Pediatric Cardiology, Seattle Children's Hospital, Seattle, WA, United States
| | - Richard A Kronmal
- Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Thor Wagner
- Division of Pediatric Infectious Diseases, Seattle Children's Hospital, Seattle, WA, United States
| | - Mariska Kemna
- Division of Pediatric Cardiology, Seattle Children's Hospital, Seattle, WA, United States
| | - Erin L Albers
- Division of Pediatric Cardiology, Seattle Children's Hospital, Seattle, WA, United States
| | - Borah Hong
- Division of Pediatric Cardiology, Seattle Children's Hospital, Seattle, WA, United States
| | | | - Kathryn Spencer
- Division of Pediatric Cardiology, Seattle Children's Hospital, Seattle, WA, United States
| | - Yuk M Law
- Division of Pediatric Cardiology, Seattle Children's Hospital, Seattle, WA, United States
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Laguë SL, Bone JN, Samuel R, Voss C, Balbacid E, Hosking MCK, Schubert S, Harris KC. Patterns of Early Coronary Artery Changes in Pediatric Heart Transplant Recipients Detected Using Optical Coherence Tomography. Circ Cardiovasc Imaging 2022; 15:e012486. [PMID: 35041446 DOI: 10.1161/circimaging.121.012486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cardiac allograft vasculopathy, the leading cause of graft failure in pediatric heart transplant recipients, is characterized by diffuse and concentric coronary intimal thickening. Early treatment yields better outcomes. While coronary angiography is the standard for cardiac allograft vasculopathy screening and diagnosis, it only identifies luminal narrowing, which occurs in more severe disease. Coronary optical coherence tomography (OCT) is a high-definition intravascular imaging modality that may offer earlier diagnosis. We used OCT to investigate coronary intimal thickening in pediatric transplant recipients and examined its (1) location (ie, vessel type and location) and (2) nature (ie, characteristics of cross-sectional and longitudinal thickening). METHODS Sites collected coronary angiography and OCT data from participants (N=258 vessel segments from 73 individuals; median age: 11.5 years [8.4-15.3]; 55% male). Images were collected from the left anterior descending, left circumflex, and right coronary arteries, and location (ie, proximal, middle, and distal) were classified using coronary angiography. RESULTS OCT identified 32 vessel segments meeting criteria for significant thickening, 88% of which were angiographically silent. Longitudinal thickening was segmental rather than global in 88%, and cross-sectional thickening was 48% eccentric and 52% concentric. Intimal thickening prevalence and severity measures did not consistently differ between coronary artery type (P=1.000) or location (P=0.248) but increased with time since transplant and age at transplant and OCT procedure. CONCLUSIONS In pediatric transplant recipients, we observed a surprisingly high prevalence of segmental and eccentric intimal thickening. Insights from intravascular imaging suggest these patterns of coronary vascular changes may precede overt cardiac allograft vasculopathy. Identifying early changes may offer opportunity for enhanced surveillance and earlier intervention.
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Affiliation(s)
- Sabine L Laguë
- Department of Pediatrics, University of British Columbia, Vancouver, Canada (S.L.L.).,Division of Cardiology, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, Canada (S.L.L., R.S., C.V., M.C.K.H., K.C.H.)
| | - Jeffrey N Bone
- British Columbia Children's Hospital Research Institute, Vancouver, Canada (J.N.B., E.B.)
| | - Rosh Samuel
- Division of Cardiology, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, Canada (S.L.L., R.S., C.V., M.C.K.H., K.C.H.)
| | - Christine Voss
- Division of Cardiology, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, Canada (S.L.L., R.S., C.V., M.C.K.H., K.C.H.)
| | - Enrique Balbacid
- British Columbia Children's Hospital Research Institute, Vancouver, Canada (J.N.B., E.B.)
| | - Martin C K Hosking
- Division of Cardiology, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, Canada (S.L.L., R.S., C.V., M.C.K.H., K.C.H.)
| | - Stephan Schubert
- Pediatric Cardiology Department, La Paz Children's University Hospital, Madrid, Spain (S.S.).,German Heart Center Berlin, Department of Congenital Heart Disease - Pediatric Cardiology, Berlin, Germany (S.S.).,Center for Congenital Heart Disease/Pediatric Cardiology, Heart, and Diabetes Center NRW, University Clinic of Ruhr-University Bochum, Germany (S.S.).,Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum Berlin, Berlin, Germany (S.S.)
| | - Kevin C Harris
- Division of Cardiology, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, Canada (S.L.L., R.S., C.V., M.C.K.H., K.C.H.)
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Cytomegalovirus Latency Exacerbated small-for-size Liver Graft Injury through Activation of CCL19/CCR7 in Hepatic Stellate Cells. Transplantation 2021; 106:519-530. [PMID: 34156186 DOI: 10.1097/tp.0000000000003846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND The interplay between cytomegalovirus (CMV) latency and graft malfunction after living donor liver transplantation (LDLT) remains poorly defined due to the complexity of clinical confounding factors. Here, we aimed to investigate the effects of CMV latency on small-for-size graft injury and to get further insight on the pathogenic role of hepatic stellate cells (HSCs) in this process. METHODS Rat orthotopic liver transplantation with small-for-size grafts was performed in a CMV latent model developed in immunocompetent Sprague Dawley (SD) rats using Priscott strain. Post-transplant graft injury including hepatocyte damage, stellate cell activation and fibrogenesis were evaluated. Differential gene expression of HSCs in response to CMV latency was screened by cDNA microarray. Clinical validation was further conducted in human biopsies. RESULTS CMV latency aggravated hepatocyte apoptosis/necrosis in the early phase, enhanced HSC expansion and graft fibrosis during the middle-late phase in small-for-size liver grafts of the rat model. cDNA microarray mining revealed CCL19/CCR7 as one of the most noteworthy pathways bridging HSC activation and liver graft injury in the presence of CMV latency. Together with CCL19 upregulation, coherent overexpression of CCR7 in accumulated HSCs was confirmed in both rat and human CMV latent recipients. Moreover, addition of CCL19 in vitro promoted HSC migration by increasing the level of matrix metalloproteinase-2 (MMP2). CONCLUSION Our data demonstrated that CMV latency aggravated early/late phase liver graft damage and fibrogenesis via CCL19/CCR7/HSCs axis. Blockade of CMV latency-related stellate cell activation may shed light on the strategy of graft protection clinically.
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Fulkerson HL, Nogalski MT, Collins-McMillen D, Yurochko AD. Overview of Human Cytomegalovirus Pathogenesis. Methods Mol Biol 2021; 2244:1-18. [PMID: 33555579 DOI: 10.1007/978-1-0716-1111-1_1] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human cytomegalovirus (HCMV) is a betaherpesvirus with a global seroprevalence of 60-90%. HCMV is the leading cause of congenital infections and poses a great health risk to immunocompromised individuals. Although HCMV infection is typically asymptomatic in the immunocompetent population, infection can result in mononucleosis and has also been associated with the development of certain cancers, as well as chronic inflammatory diseases such as various cardiovascular diseases. In immunocompromised patients, including AIDS patients, transplant recipients, and developing fetuses, HCMV infection is associated with increased rates of morbidity and mortality. Currently there is no vaccine for HCMV and there is a need for new pharmacological treatments. Ongoing research seeks to further define the complex aspects of HCMV pathogenesis, which could potentially lead to the generation of new therapeutics to mitigate the disease states associated with HCMV infection. The following chapter reviews the advancements in our understanding of HCMV pathogenesis in the immunocompetent and immunocompromised hosts.
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Affiliation(s)
- Heather L Fulkerson
- Department of Microbiology & Immunology, Center for Molecular and Tumor Virology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
- Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Maciej T Nogalski
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | | | - Andrew D Yurochko
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
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Das BB, Prusty BK, Niu J, Sue PK. Cytomegalovirus infection and allograft rejection among pediatric heart transplant recipients in the era of valganciclovir prophylaxis. Pediatr Transplant 2020; 24:e13750. [PMID: 32573886 DOI: 10.1111/petr.13750] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 04/27/2020] [Accepted: 05/03/2020] [Indexed: 12/28/2022]
Abstract
CMV infection remains a significant cause of morbidity among pediatric HTx recipients We explored the implications of CMV infection on post-transplant outcomes among CMV risk-stratified pediatric HTx recipients receiving VGC prophylaxis. Children who underwent HTx between January 2010 and October 2016 were stratified according to CMV risk at time of transplant and evaluated for evidence of post-transplant CMV infection, rejection, CAV, and graft loss. Among 97 children, 41 (42%) were considered HR or IR risk for CMV infection and received VGC prophylaxis. CMV DNAemia was observed in 34% of children, including 71% HR, 40% IR, and 18% LR individuals. Median time to CMV DNAemia following VGC prophylaxis was 32D among HR vs 277D in IR subjects (P = .042). No difference in overall graft loss was noted among groups, but CMV HR children had decreased rejection-free survival (3.5 years) compared to IR (6 years, P = .015) and LR children (8 years, P = .0003). CMV was noted on EMB in 13% of children but was not associated with increased CAV, rejection or graft loss. High-risk CMV status was associated with decreased time to CMV infection despite VGC prophylaxis, compared to IR, and decreased rejection-free survival times compared to both IR and LR recipients. Detection of CMV on EMB was not associated with increased rejection, CAV or graft loss. Additional studies are needed to explore the impact of CMV infection on rejection-free survival in HTx recipients.
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Affiliation(s)
- Bibhuti B Das
- Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Bhupesh K Prusty
- Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany
| | - Jianli Niu
- Office of Human Research, Memorial Healthcare System, Hollywood, Florida, USA
| | - Paul K Sue
- Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Habibi S, Ghaffarpasand E, Shojaei F, Alihashemi M, Kahe F, Zahedi Tajrishi F, Chi G. Prognostic Value of Biomarkers in Cardiac Allograft Vasculopathy following Heart Transplantation: A Literature Review. Cardiology 2020; 145:693-702. [PMID: 32892195 DOI: 10.1159/000509630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 06/23/2020] [Indexed: 11/19/2022]
Abstract
Cardiac allograft vasculopathy (CAV), also known as cardiac transplant vasculopathy, is a major determinant of long-term survival among cardiac transplantation recipients. Histologically, CAV is featured by diffuse, concentric thickening of the vascular wall, and primarily affects large and small epicardial coronary arteries, intramyocardial arteries, and veins. Owing to graft denervation, CAV typically follows an insidious course, and patients may not experience classic angina symptoms but instead present with progressive heart failure or ventricular arrhythmias. Recent studies on biomarkers have furthered the knowledge concerning the prediction and prognosis of CAV. Given its association with metabolic, thrombotic, inflammatory, and immunologic markers, CAV is likely to represent a complex multifactorial process that involves both immune-mediated and non-immune-mediated pathways. In order to identify the high-risk patients that would benefit from early intervention, future research is warranted to examine the usefulness of a biomarker panel in CAV risk stratification.
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Affiliation(s)
- Shaghayegh Habibi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Eiman Ghaffarpasand
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Fahimehalsadat Shojaei
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Mahda Alihashemi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Farima Kahe
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Gerald Chi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA,
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Asante-Korang A, Carapellucci J, Krasnopero D, Brown B, Kiskaddon A, Wisotzkey B, Blyumin G, Berman DM, Namtu K. Resource utilization of cytomegalovirus immune globulin in prevention and treatment of cytomegalovirus infection in pediatric heart transplantation. Clin Transplant 2019; 33:e13750. [PMID: 31692121 DOI: 10.1111/ctr.13750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 10/18/2019] [Accepted: 10/25/2019] [Indexed: 11/26/2022]
Abstract
BACKGROUND There is debate whether cytomegalovirus immunoglobulin (CMV-Ig) is also needed for CMV prevention in heart transplant recipients in the era of good anti-viral drugs. METHODS We conducted a cost-savings quality initiative on CMV-Ig eventually leading to discontinuation of routine use of CMV-Ig for CMV prevention. Subsequently, a retrospective cohort study was conducted, comparing patients in cohort I (CMV-Ig plus anti-viral drugs, 2013-2015) to cohort II (anti-virals alone, 2015-2017). The medication acquisition costs and outcomes of CMV infection were assessed. RESULTS There were 39 total patients: 22/39(56%) in cohort I, with mean follow-up of 35.14 ± 17.38 months and 17/39(44%) in cohort II, mean follow-up of 19.12 ± 7.08 months. In cohort I, 5/22(22.7%) patients died from causes unrelated to CMV and 0/17 in cohort II died. There were 5/22(22.7%) patients in cohort I, and 2/17(9%) patients in cohort II that developed CMV infection (P = .508). Freedom from rejection was 81.8% (18/22) in cohort I, and 71% (12/17) in cohort II (P = .46), and 100% for allograft vasculopathy. There was significant reduction in medication acquisition cost following the protocol change of $260 839 or $15 343 per patient. CONCLUSION Our study demonstrated an acquisition cost savings with similar clinical outcomes utilizing anti-viral CMV prophylaxis alone vs anti-viral prophylaxis plus CMV-Ig.
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Affiliation(s)
- Alfred Asante-Korang
- Division of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
| | - Jennifer Carapellucci
- Division of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
| | - Diane Krasnopero
- Division of Cardiology, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Brian Brown
- Division of Pharmacy, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
| | - Amy Kiskaddon
- Division of Pharmacy, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
| | - Bethany Wisotzkey
- Division of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
| | - Gabriella Blyumin
- Department of Pharmacy, Nicklaus Children's Hospital, Miami, FL, USA
| | - David M Berman
- Division of Infectious Diseases, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
| | - Katie Namtu
- Division of Pharmacy, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA
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Abstract
BACKGROUND Cytomegalovirus (CMV) infection is implicated in endothelial dysfunction and graft damage after pediatric heart transplantation. CMV-specific immune responses are thought to be necessary for CMV viral control but there is little data in pediatric heart transplantation. METHODS We studied 28 consecutive pediatric heart transplant recipients for 1 year posttransplant. CMV T-cell expressing IFN-γ, TNF-α, and IL-2 in response to ex vivo stimulation with CMV lysates or peptides were measured. Circulating cytokines were measured in plasma. Generalized Additive Models were applied to the data to model changes of cell population dynamics over time. RESULTS CMV-specific T cell-mediated responses were impaired in the first 8 weeks posttransplant. During this period, 25% of patients had CMV viremia, of which those with VLs of 10 000 or more CMV deoxyribonucleic acid copies/mL were given ganciclovir. In this group, the frequency of CD4+ and CD8+ T cells producing IFN-γ and the CD8+CD57+ granzyme B+ T-cell population increased at 12 to 24 weeks and remained elevated for the duration of the study. CONCLUSIONS We have shown that CMV viremia is associated with CMV-specific immune responses and increased CD8+CD57+ granzyme B+ cells at 1 year posttransplant; however, early responses were not predictive of impending CMV viremia. It remains to be seen if the early CMV immune response detected is associated with endothelial and allograft damage, in light of previous studies demonstrating increased vasculopathy in pediatric patients with CMV viremia.
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11
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The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2019; 102:900-931. [PMID: 29596116 DOI: 10.1097/tp.0000000000002191] [Citation(s) in RCA: 812] [Impact Index Per Article: 135.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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 approach 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 of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations.
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Britt WJ, Prichard MN. New therapies for human cytomegalovirus infections. Antiviral Res 2018; 159:153-174. [PMID: 30227153 DOI: 10.1016/j.antiviral.2018.09.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/28/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today's standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease. While ganciclovir remains the therapy of choice, additional drugs that inhibit novel molecular targets, such as letermovir, will be required as highly effective combination therapies are developed not only for the treatment of immunocompromised hosts, but also for congenitally infected infants. Sustained efforts, largely in the biotech industry and academia, have identified additional highly active lead compounds that have progressed into clinical studies with varying levels of success and at least two have the potential to be approved in the near future. Some of the new drugs in the pipeline inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapeutic regimens. Here, we will describe some of the unique features of HCMV biology and discuss their effect on therapeutic needs. Existing drugs will also be discussed and some of the more promising candidates will be reviewed with an emphasis on those progressing through clinical studies. The in vitro and in vivo antiviral activity, spectrum of antiviral activity, and mechanism of action of new compounds will be reviewed to provide an update on potential new therapies for HCMV infections that have progressed significantly in recent years.
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Affiliation(s)
- William J Britt
- Department of Pediatrics, University of Alabama School of Medicine, Birmingham AL 35233-1711, USA
| | - Mark N Prichard
- Department of Pediatrics, University of Alabama School of Medicine, Birmingham AL 35233-1711, USA.
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13
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Watanabe K, Karimpour-Fard A, Michael A, Miyamoto SD, Nakano SJ. Elevated serum vascular endothelial growth factor and development of cardiac allograft vasculopathy in children. J Heart Lung Transplant 2018; 37:1075-1082. [PMID: 29954686 PMCID: PMC6261433 DOI: 10.1016/j.healun.2018.04.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 04/19/2018] [Accepted: 04/25/2018] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is a leading cause of retransplantation and death in pediatric heart transplant recipients. Our aim was to evaluate the association between serum vascular endothelial growth factor-A (VEGF) and CAV development in the pediatric heart transplant population. METHODS In this retrospective study performed at a university hospital, VEGF concentrations were measured by enzyme-linked immunosorbent assay in banked serum from pediatric heart transplant recipients undergoing routine cardiac catheterization. In subjects with CAV (n = 29), samples were obtained at 2 time-points: before CAV diagnosis (pre-CAV) and at the time of initial CAV diagnosis (CAV). In subjects without CAV (no-CAV, n = 16), only 1 time-point was used. VEGF concentrations (n = 74) were assayed in duplicate. RESULTS Serum VEGF is elevated in pediatric heart transplant recipients before catheter-based diagnosis of CAV (no-CAV mean: 144.0 ± 89.05 pg/ml; pre-CAV mean: 316.2 ± 118.3 pg/ml; p = 0.0002). Receiver-operating characteristic curve analysis of pre-CAV VEGF levels demonstrated an area under the curve of 87.7% (p = 0.0002), with a VEGF level of 226.3 pg/ml predicting CAV development with 77.8% sensitivity and 91.7% specificity. VEGF is similarly elevated in subjects with angiographically diagnosed CAV and in those with normal angiography but intravascular ultrasound (IVUS) evidence of CAV. CONCLUSIONS The increase in serum VEGF before onset of detectable CAV is fundamental to its utility as a predictive biomarker and suggests further investigations of VEGF in the pathogenesis of CAV are warranted in the pediatric heart transplant population.
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Affiliation(s)
- Kae Watanabe
- Division of Cardiology, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
| | - Anis Karimpour-Fard
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alix Michael
- Division of Cardiology, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
| | - Shelley D Miyamoto
- Division of Cardiology, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
| | - Stephanie J Nakano
- Division of Cardiology, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
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Luc JGY, Choi JH, Rizvi SSA, Phan K, Moncho Escrivà E, Patel S, Reeves GR, Boyle AJ, Entwistle JW, Morris RJ, Massey HT, Tchantchaleishvili V. Percutaneous coronary intervention versus coronary artery bypass grafting in heart transplant recipients with coronary allograft vasculopathy: a systematic review and meta-analysis of 1,520 patients. Ann Cardiothorac Surg 2018; 7:19-30. [PMID: 29492381 DOI: 10.21037/acs.2018.01.10] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background Transplant coronary artery vasculopathy (TCAV) is the major cause of late allograft failure and death in heart transplant recipients. The aim of this systematic review was to examine the outcomes of percutaneous coronary interventions (PCIs) as compared to coronary artery bypass grafting (CABG) surgery in the management of TCAV. Our secondary objective was to compare the use and outcomes of drug eluting stents (DES) as compared to bare metal stents (BMS) in this patient population. Methods Electronic search was performed to identify all studies in the English literature examining PCI as compared to CABG for TCAV in heart transplant recipients. All identified articles were systematically assessed for inclusion and exclusion criteria. Results Of the 4,989 studies identified, 29 studies were included. Among 1,520 patients who developed TCAV, 1,470 patients underwent PCI and 50 patients underwent CABG. There were no significant differences in baseline demographics and comorbidities among the PCI and CABG cohorts. Compared to the PCI cohort, patients who underwent CABG had a higher early mortality (CABG 36.4% vs. PCI 4.3%, P<0.001) and overall mortality (CABG 42.3% vs. PCI 21.4%, P=0.049). When comparing DES versus BMS cohorts, there were no significant differences in the rate of in-stent stenosis (DES 14.5% vs. BMS 24.4%, P=0.476), overall mortality (DES 17.4% vs. BMS 30.8%, P=0.302) or cardiac related mortality (DES 7.7% vs. BMS 21.8%, P=0.415). Conclusions CABG and PCI are both feasible modalities for revascularization in patients with TCAV where PCI is associated with lower mortality. There were no differences in outcomes among patients who underwent PCI with DES as compared to BMS. Potential bias may exist due to heterogeneity in available data. Further studies are needed to delineate evidence-based guidelines to tailor the appropriate therapy, CABG or PCI, to the appropriate patient.
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Affiliation(s)
- Jessica G Y Luc
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Jae Hwan Choi
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Syed-Saif Abbas Rizvi
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Kevin Phan
- Faculty of Medicine, University of New South Wales, Sydney, Australia
| | | | - Sinal Patel
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Gordon R Reeves
- Division of Cardiology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Andrew J Boyle
- Division of Cardiology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - John W Entwistle
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Rohinton J Morris
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - H Todd Massey
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Barge-Caballero E, Barbeito-Caamaño C, Barge-Caballero G, Couto-Mallón D, Paniagua-Martín MJ, Marzoa-Rivas R, Solla-Buceta M, Estévez-Cid F, Herrera-Noreña JM, Cuenca-Castillo JJ, Vázquez-Rodríguez JM, Crespo-Leiro MG. Estado serológico frente a Toxoplasma gondii en receptores de trasplante cardiaco: ¿un factor pronóstico independiente? Rev Esp Cardiol 2016. [DOI: 10.1016/j.recesp.2016.04.050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Li L, Liu M, Kang L, Li Y, Dai Z, Wang B, Liu S, Chen L, Tan Y, Wu G. HHEX: A Crosstalker between HCMV Infection and Proliferation of VSMCs. Front Cell Infect Microbiol 2016; 6:169. [PMID: 27965937 PMCID: PMC5127840 DOI: 10.3389/fcimb.2016.00169] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 11/15/2016] [Indexed: 01/08/2023] Open
Abstract
Objective: The study was designed to evaluate the role of Human cytomegalovirus (HCMV) infection on homebox (HOX) gene expression and the effects of overexpression of HOX genes on proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Methods: Viral infection was verified by observation of cytopathic effects through inverted microscopy, viral particles by electron microscopy and HCMV IE gene amplification by RT-PCR. cDNA profiling technology was used to screen expression of HOX genes after HCMV infection in VSMCs. Abnormal expression of Haematopoietically-expressed homeobox (HHEX) was selected to construct over-expressed vector and transfected into VSMCs. The effects of over expression of HHEX on cell proliferation and apoptosis of VSMCs were assayed by flow cytometry. Apoptosis and proliferation-associated genes were also assayed by RT-PCR. Results: Multiple HOX gene expression levels had obvious changes after HCMV infection, among which expression of HHEX gene increased obviously at 24, 48, and 72 h after infection. Over expression of HHEX can promote VSMCs proliferation by promoting G0/G1 phase cells into S phase and inhibit VSMCs apoptosis. HHEX inhibited the expression of apoptosis-associated caspase 2 and caspase3 and promoted the expression of cell cycle-related genes such as CDK2 and CDK6, CyclinB2 and CyclinD2. Conclusion: HHEX over expression induced by HCMV infection closely associated with vascular proliferative diseases.
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Affiliation(s)
- Lingfang Li
- Department of Vasculocardiology, Xiangya Hospital, Central South University Changsha, China
| | - Meitong Liu
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Leitao Kang
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Yifan Li
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Ziyu Dai
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Bing Wang
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Shuiping Liu
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Liyu Chen
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Yurong Tan
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
| | - Guojun Wu
- Department of Microbiology, School of Basic Medical Sciences, Central South University Changsha, China
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17
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Barge-Caballero E, Barbeito-Caamaño C, Barge-Caballero G, Couto-Mallón D, Paniagua-Martín MJ, Marzoa-Rivas R, Solla-Buceta M, Estévez-Cid F, Herrera-Noreña JM, Cuenca-Castillo JJ, Vázquez-Rodríguez JM, Crespo-Leiro MG. Toxoplasma Gondii Serostatus in Heart Transplant Recipients: Is It an Independent Prognostic Factor? ACTA ACUST UNITED AC 2016; 69:1160-1166. [PMID: 27597125 DOI: 10.1016/j.rec.2016.04.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 04/05/2016] [Indexed: 11/30/2022]
Abstract
INTRODUCTION AND OBJECTIVES To assess the potential association between recipient Toxoplasma gondii serostatus and outcomes after heart transplant (HT). METHODS We conducted a retrospective single-center study of 657 HT recipients from 1991 to 2015. Survival and the incidence of adverse clinical events of T. gondii-seropositive (n = 481) vs T. gondii-seronegative (n = 176) recipients were compared by means of 2 different multivariable Cox regression models. Model 1 included solely age and sex, and model 2 included other potential confounders. RESULTS Over a median follow-up of 2903 days (interquartile range: 898-4757), 250 seropositive recipients (52%) and 72 seronegative recipients (41%) died. Univariable analysis showed increased posttransplant mortality among T. gondii-seropositive recipients (hazard ratio [HR] = 1.31; 95% confidence interval [95%CI], 1,00-1.70). After multivariable adjustment, the statistical significance of this association was lost (model 1: HR = 1.09; 95%CI, 0.83-1.43; model 2:HR = 1.12; 95%CI, 0.85-1.47). Recipient T. gondii seropositivity was independently associated with an increased risk of acute rejection (model 1: HR = 1.36; 95%CI, 1.06-1.74; model 2: HR = 1.29; 95%CI, 1.01-1.66). Multivariable models showed no statistically significant impact of recipient T. gondii serostatus on the incidence of infection, malignancy, coronary allograft vasculopathy, or the composite outcome of cardiac death or retransplant. No significant association was found between donor-recipient T. gondii serostatus matching and posttransplant outcome. CONCLUSIONS In this study, recipient T. gondii serostatus was not an independent predictor of long-term post-HT outcome.
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Affiliation(s)
- Eduardo Barge-Caballero
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain.
| | - Cayetana Barbeito-Caamaño
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | - Gonzalo Barge-Caballero
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | - David Couto-Mallón
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | - María J Paniagua-Martín
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | - Raquel Marzoa-Rivas
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | - Miguel Solla-Buceta
- Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Servicio de Medicina Intensiva, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - Francisco Estévez-Cid
- Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Servicio de Cirugía Cardiaca, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - José M Herrera-Noreña
- Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Servicio de Cirugía Cardiaca, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - José J Cuenca-Castillo
- Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Servicio de Cirugía Cardiaca, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - José M Vázquez-Rodríguez
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | - María G Crespo-Leiro
- Servicio de Cardiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
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Torre-Cisneros J, Aguado J, Caston J, Almenar L, Alonso A, Cantisán S, Carratalá J, Cervera C, Cordero E, Fariñas M, Fernández-Ruiz M, Fortún J, Frauca E, Gavaldá J, Hernández D, Herrero I, Len O, Lopez-Medrano F, Manito N, Marcos M, Martín-Dávila P, Monforte V, Montejo M, Moreno A, Muñoz P, Navarro D, Pérez-Romero P, Rodriguez-Bernot A, Rumbao J, San Juan R, Vaquero J, Vidal E. Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev (Orlando) 2016; 30:119-43. [DOI: 10.1016/j.trre.2016.04.001] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 04/02/2016] [Accepted: 04/04/2016] [Indexed: 02/06/2023]
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Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation. J Heart Lung Transplant 2015; 34:1112-9. [DOI: 10.1016/j.healun.2015.03.015] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 02/16/2015] [Accepted: 03/16/2015] [Indexed: 11/17/2022] Open
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20
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Dedieu N, Greil G, Wong J, Fenton M, Burch M, Hussain T. Diagnosis and management of coronary allograft vasculopathy in children and adolescents. World J Transplant 2014; 4:276-293. [PMID: 25540736 PMCID: PMC4274597 DOI: 10.5500/wjt.v4.i4.276] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 08/12/2014] [Accepted: 09/17/2014] [Indexed: 02/05/2023] Open
Abstract
Coronary allograft vasculopathy remains one of the leading causes of death beyond the first year post transplant. As a result of denervation following transplantation, patients lack ischaemic symptoms and presentation is often late when the graft is already compromised. Current diagnostic tools are rather invasive, or in case of angiography, significantly lack sensitivity. Therefore a non-invasive tool that could allow early diagnosis would be invaluable.This paper review the disease form its different diagnosis techniques,including new and less invasive diagnostic tools to its pharmacological management and possible treatments.
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21
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Roman A, Manito N, Campistol JM, Cuervas-Mons V, Almenar L, Arias M, Casafont F, del Castillo D, Crespo-Leiro MG, Delgado JF, Herrero JI, Jara P, Morales JM, Navarro M, Oppenheimer F, Prieto M, Pulpón LA, Rimola A, Serón D, Ussetti P. The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients. Transplant Rev (Orlando) 2014; 28:84-91. [DOI: 10.1016/j.trre.2014.01.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 01/19/2014] [Indexed: 01/10/2023]
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Abstract
Human cytomegalovirus (HCMV) is a human pathogen that infects greater than 50 % of the human population. HCMV infection is usually asymptomatic in most individuals. That is, primary infection or reactivation of latent virus is generally clinically silent. HCMV infection, however, is associated with significant morbidity and mortality in the immunocompromised and chronic inflammatory diseases in the immunocompetent. In immunocompromised individuals (acquired immune deficiency syndrome and transplant patients, developing children (in utero), and cancer patients undergoing chemotherapy), HCMV infection increases morbidity and mortality. In those individuals with a normal immune system, HCMV infection is also associated with a risk of serious disease, as viral infection is now considered to be a strong risk factor for the development of various vascular diseases and to be associated with some types of tumor development. Intense research is currently being undertaken to better understand the mechanisms of viral pathogenesis that are briefly discussed in this chapter.
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Affiliation(s)
- Maciej T Nogalski
- Department of Microbiology & Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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23
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Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, Humar A. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013; 96:333-60. [PMID: 23896556 DOI: 10.1097/tp.0b013e31829df29d] [Citation(s) in RCA: 566] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cytomegalovirus (CMV) continues to be one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes. Management of CMV varies considerably among transplant centers but has been become more standardized by publication of consensus guidelines by the Infectious Diseases Section of The Transplantation Society. An international panel of experts was reconvened in October 2012 to revise and expand evidence and expert opinion-based consensus guidelines on CMV management, including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues. The following report summarizes the recommendations.
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Affiliation(s)
- Camille N Kotton
- Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
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Chen CK, Dipchand AI. The current state and key issues of pediatric heart transplantation. INDIAN JOURNAL OF TRANSPLANTATION 2013. [DOI: 10.1016/j.ijt.2013.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Hussain T, Fenton M, Peel SA, Wiethoff AJ, Taylor A, Muthurangu V, Razavi R, Botnar RM, Burch M, Greil GF. Detection and grading of coronary allograft vasculopathy in children with contrast-enhanced magnetic resonance imaging of the coronary vessel wall. Circ Cardiovasc Imaging 2012; 6:91-8. [PMID: 23223637 DOI: 10.1161/circimaging.112.975797] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Coronary allograft vasculopathy is the leading cause of late death after heart transplantation in children. It is poorly detected by conventional angiography. Intravascular ultrasound is invasive and costly. This study shows that magnetic resonance imaging (MRI) late gadolinium enhancement (LGE) of the coronary vessel wall can detect and grade coronary allograft vasculopathy. METHODS AND RESULTS Twenty-four children (10 male; age range, 9-17 years) underwent coronary angiography, intravascular ultrasound, and MRI. Maximal intimal thickness and mean intimal index were recorded. MRI included coronary magnetic resonance angiogram and LGE vessel wall imaging with 1.5 T (n=12) and 3.0 T (n=12). Ten healthy control subjects also underwent LGE MRI. Mean time posttransplantation was 5.5 years (range, 0.25-14 years). Seven patients had Stanford grade IV coronary allograft vasculopathy on intravascular ultrasound, 3 of whom had angiographic disease. Maximal intimal thickness and mean intimal index were 0.73±0.50 mm and 20.9±10.6%, respectively. On MRI, mean diameter of enhancement of vessel wall was 6.57±4.91 mm, and mean enhancement index (indexed to vessel lumen size) was 1.10±1.72. The control group showed little or no LGE. Correlation of LGE with maximal intimal thickness using the Pearson coefficient was 0.80 (P<0.001) and with mean intimal index was 0.92 (P<0.001). An MRI diameter >7.5 mm gave 86% sensitivity and 93% specificity. CONCLUSIONS LGE scores correlate well with traditional intravascular ultrasound measures. These promising early results encourage larger-scale clinical studies to investigate whether LGE MRI will allow closer follow-up and better prevention of coronary allograft vasculopathy in children.
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Lin A, Worley S, Brubaker J, Boyle G, Nasman C, Sabella C, Danziger-Isakov LA. Assessment of Cytomegalovirus Hybrid Preventative Strategy in Pediatric Heart Transplant Patients. J Pediatric Infect Dis Soc 2012; 1:278-83. [PMID: 26619420 DOI: 10.1093/jpids/pis056] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Accepted: 03/27/2012] [Indexed: 11/12/2022]
Abstract
BACKGROUND Prevention strategies for cytomegalovirus (CMV) in pediatric transplant recipients are sparsely reported. A hybrid strategy that combines prophylaxis with preemptive therapy using serial CMV viral load monitoring is an emerging option. We report our clinical outcomes with a hybrid strategy in pediatric heart transplant recipients. METHODS A retrospective chart review was performed for pediatric heart transplant recipients who received a hybrid strategy of 2-4 weeks intravenous ganciclovir followed by serial whole blood CMV monitoring from 2002 to 2010. Subject demographics, medications, drug levels, serial CMV viral loads, intravascular ultrasound and angiography reports, and histopathology were collected. Descriptive statistics and patient groups were compared using χ(2), Fisher's exact, and Wilcoxon rank-sum tests. RESULTS Twelve females and 13 males, ranging from 4 months to 19 years of age, underwent 26 heart transplants. Mean follow-up was 39 months (range, 5-94 months). Fourteen (54%) subjects were CMV donor (D) + /recipient (R) - , 8 (31%) were D + /R + , and 4 (15%) were D - /R + . Six subjects (23%) died of complications unrelated to CMV. Median prophylaxis duration was 25 days (range, 7-70 days). Ten (38%) subjects developed CMV infection: 1 subject had 2 episodes of CMV syndrome, and 1 subject had 2 episodes CMV. Although 6 of 14 patients with coronary artery vasculopathy had prior CMV, no association was found (P = .81). Median time to first CMV DNAemia was 2.3 months (range, 9 days to 24.8 months). Median time to viral load clearance was 29 days (range, 4-233 days). In addition, 25 D - /R- patients were transplanted and received no prophylaxis; 2 (8%) patients developed CMV infection. CONCLUSIONS Pediatric heart transplant recipients who were at risk for CMV and treated with a novel preventative hybrid strategy developed CMV infection, syndrome, and disease at rates similar to those reported in literature for prophylactic strategies.
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Affiliation(s)
- Angela Lin
- Case Western Reserve University School of Medicine, Cleveland
| | - Sarah Worley
- Department of Quantitative Health Sciences, Cleveland Clinic, and
| | - Jennifer Brubaker
- Department of Pediatric Cardiology, Pediatric Institute and The Children's Hospital at Cleveland Clinic
| | - Gerard Boyle
- Department of Pediatric Cardiology, Pediatric Institute and The Children's Hospital at Cleveland Clinic
| | - Colleen Nasman
- Department of Pediatric Cardiology, Pediatric Institute and The Children's Hospital at Cleveland Clinic
| | - Camille Sabella
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Ohio
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Abstract
The presence and persistence of alloantigen is necessary for graft-specific T-cell-mediated immunity. However, specificity comprises only a single facet of an extremely complex process. Evidence is accruing to suggest that immunogenicity could be manipulated by endogenous ligands released during tissue injury. Stress molecules are significantly up-regulated following transplantation and stimulate conserved receptors on a range of leucocytes, including dendritic cells (DCs). The DCs are essential for co-stimulation and the induction of adaptive immunity. Stress signals can act as an adjuvant leading to DC maturation and activation. DCs stimulated by endogens exhibit enhanced alloantigen presentation, co-stimulation and production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. Inflammasomes have a major role in IL-1β/IL-18 production and secretion, and can be stimulated by endogens. Importantly, the polarization toward inflammatory T helper type 17 cells as opposed to regulatory T cells is dependent upon, among other factors, IL-1β. This highlights an important differentiation pathway that may be influenced by endogenous signals. Minimizing graft damage and stress expression should hypothetically be advantageous, and we feel that this area warrants further research, and may provide novel treatment modalities with potential clinical benefit.
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Affiliation(s)
- William R Critchley
- The Transplant Centre, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, The University of Manchester, Manchester, UK
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28
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Early cardiac allograft vasculopathy: are the viruses to blame? Case Rep Med 2012; 2012:734074. [PMID: 22701124 PMCID: PMC3369528 DOI: 10.1155/2012/734074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 04/11/2012] [Indexed: 11/23/2022] Open
Abstract
This paper describes a case of early (7 months after transplant) cardiac allograft vasculopathy. This-43-year-old (CMV positive, EBV negative) female patient underwent an orthotopic heart transplant with a (CMV negative, EBV positive) donor heart. She had a history of herpes zoster infection and postherpetic neuralgia in the past. The patient's panel reactive antibodies had been almost undetectable on routine surveillance testing, and her surveillance endomyocardial biopsies apart from a few episodes of mild-to-moderate acute cellular rejection (treated adequately with steroids) never showed any evidence of humoral rejection. The postoperative course was complicated by multiple admissions for upper respiratory symptoms, and the patient tested positive for entero, rhino, and coronaviruses serologies. During her last admission (seven months postoperatively) the patient developed mild left ventricular dysfunction with an ejection fraction of 40%. The patient's endomyocardial biopsy done at that time revealed concentric intimal proliferation and inflammation resulting in near-total luminal occlusion in the epicardial and the intramyocardial coronary vessels, suggestive of graft vasculopathy with no evidence of rejection, and the patient had a fatal ventricular arrhythmia.
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Ross SA, Novak Z, Pati S, Boppana SB. Overview of the diagnosis of cytomegalovirus infection. Infect Disord Drug Targets 2012; 11:466-74. [PMID: 21827433 DOI: 10.2174/187152611797636703] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Accepted: 07/19/2010] [Indexed: 02/06/2023]
Abstract
Cytomegalovirus (CMV) is recognized as the most common congenital viral infection in humans and an important cause of morbidity and mortality in immunocompromised hosts. This recognition of the clinical importance of invasive CMV disease in the setting of immunodeficiency and in children with congenital CMV infection has led to the development of new diagnostic procedures for the rapid identification of CMV. Diagnosis of acute maternal CMV infection by the presence of immunoglobulin (Ig)M and low-avidity IgG requires confirmation of fetal infection, which is typically performed using polymerase chain reaction (PCR) assays for CMV on amniotic fluid. Viral culture of the urine and saliva obtained within the first two weeks of life continues to be the gold standard for diagnosis of congenitally-infected infants. PCR assays of dried blood spots from newborns have been shown to lack sufficient sensitivity for the identification of most neonates with congenital CMV infection for universal screening purposes. However, saliva PCR assays are currently being assessed as a useful screening method for congenital CMV infection. In the immunocompromised host, newer rapid diagnostic assays, such as phosphoprotein 65 antigenemia and CMV real-time PCR of blood or plasma have allowed for preemptive treatment, reducing morbidity and mortality. However, lack of standardized real-time PCR protocols hinders the comparison of data from different centers and the development of uniform guidelines for the management of invasive CMV infections in immunocompromised individuals.
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Affiliation(s)
- S A Ross
- Departments of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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Jeewa A, Dreyer WJ, Kearney DL, Denfield SW. The Presentation and Diagnosis of Coronary Allograft Vasculopathy in Pediatric Heart Transplant Recipients. CONGENIT HEART DIS 2012; 7:302-11. [DOI: 10.1111/j.1747-0803.2012.00656.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Schumacher KR, Gajarski RJ, Urschel S. Pediatric Coronary Allograft Vasculopathy-A Review of Pathogenesis and Risk Factors. CONGENIT HEART DIS 2011; 7:312-23. [DOI: 10.1111/j.1747-0803.2011.00601.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Varani S, Landini MP. Cytomegalovirus-induced immunopathology and its clinical consequences. HERPESVIRIDAE 2011; 2:6. [PMID: 21473750 PMCID: PMC3082217 DOI: 10.1186/2042-4280-2-6] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Accepted: 04/07/2011] [Indexed: 12/23/2022]
Abstract
Human cytomegalovirus (CMV) is a ubiquitous DNA virus that causes severe disease in patients with immature or impaired immune systems. During active infection, CMV modulates host immunity, and CMV-infected patients often develop signs of immune dysfunction, such as immunosuppression and autoimmune phenomena. Furthermore, active viral infection has been observed in several autoimmune diseases, and case reports have linked primary CMV infection and the onset of autoimmune disorders. In addition, CMV infection promotes allograft rejection and graft-versus-host disease in solid organ and bone marrow transplant recipients, respectively, further implicating CMV in the genesis and maintenance of immunopathological phenomena. The mechanisms by which CMV could induce inhibition of host defense, inflammation, and autoimmunity are discussed, as is the treatment of virus-induced immunopathology with antivirals.
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Affiliation(s)
- Stefania Varani
- Section of Microbiology, Department of Hematology and Oncology, University of Bologna, Bologna, Italy
| | - Maria Paola Landini
- Section of Microbiology, Department of Hematology and Oncology, University of Bologna, Bologna, Italy
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Cytomegalovirus Prevention and Long-Term Recipient and Graft Survival in Pediatric Heart Transplant Recipients. Transplantation 2010; 90:1432-8. [DOI: 10.1097/tp.0b013e3181ffba7e] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O'Connell J, Rogers J, Ross H, Russell S, Vanhaecke J, Russell S, Vanhaecke J. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29:914-56. [PMID: 20643330 DOI: 10.1016/j.healun.2010.05.034] [Citation(s) in RCA: 1215] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2010] [Accepted: 05/31/2010] [Indexed: 12/26/2022] Open
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Karamichalis JM, Miyamoto SD, Campbell DN, Smith J, McFann KK, Clark S, Pietra B, Mitchell MB. Pediatric cardiac retransplant: differing patterns of primary graft failure by age at first transplant. J Thorac Cardiovasc Surg 2010; 141:223-30. [PMID: 21047651 DOI: 10.1016/j.jtcvs.2010.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 08/05/2010] [Accepted: 09/08/2010] [Indexed: 10/18/2022]
Abstract
OBJECTIVE This study compared graft failure leading to retransplant in infants versus older children at initial heart transplant. METHODS Twenty-six retransplant recipients were compared by age at first transplant: infant group (<1 year) and pediatric group (≥1 year). RESULTS Early retransplant survival was 92%. Retransplant survivals at 1, 3, and 5 years were 83%, 74%, and 67%. There were 15 infant and 11 pediatric patients. First transplant ages were 0.4 ± 0.3 vs. 8.5 ± 5.7 years in infant and pediatric groups, respectively (P < .01). First graft rejection episodes were more common in pediatric group (4.8 ± 2.5 vs 3.1 ± 2.1, P = .032), and rejection rate was higher (1.5 ± 1.1 vs 0.4 ± 0.4, P = .0024). Median first graft survival was longer in infant group (10.7 years vs 3.9 years, P < .001). Recurrent cellular rejection was retransplant indication in 40% of infant group versus 91% of pediatric group (P < .05). Cardiac allograft vasculopathy was more prevalent in infant group (73% vs 20% in pediatric group, P = .032). CONCLUSIONS Infant heart transplant recipients had longer primary graft survival, fewer cellular rejection episodes, and higher incidence of cardiac allograft vasculopathy relative to older graft recipients requiring retransplant. Advantages in adaptive immunity in infant heart recipients confer improved primary graft survival, but longer graft life in these patients is limited by cardiac allograft vasculopathy. Older recipient first graft failure was rejection related, and shorter graft life probably limited development of cardiac allograft vasculopathy.
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Eid AJ, Razonable RR. New developments in the management of cytomegalovirus infection after solid organ transplantation. Drugs 2010; 70:965-81. [PMID: 20481654 DOI: 10.2165/10898540-000000000-00000] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite remarkable advances in the diagnostic and therapeutic modalities for its management, cytomegalovirus (CMV) remains one of the most important pathogens impacting on the outcome of transplantation. Not only does CMV directly cause morbidity and occasional mortality, it also influences many short-term and long-term indirect effects that collectively contribute to reduced allograft and patient survival. Prevention of CMV infection and disease is therefore key in ensuring the successful outcome of solid organ transplantation (SOT). In this regard, antiviral prophylaxis and pre-emptive therapy are similarly effective in preventing CMV disease after transplantation. However, current guidelines prefer antiviral prophylaxis over pre-emptive therapy in preventing CMV disease in high-risk SOT recipients, such as CMV-seronegative recipients of organs from CMV-seropositive donors (CMV D+/R-), and lung, intestinal and pancreas transplant recipients. Antiviral prophylaxis has the benefits of reducing not only the incidence of CMV disease, but also the indirect effects of CMV on allograft and patient survival. The major drawback of antiviral prophylaxis is delayed-onset CMV disease, which occurs in 15-38% of CMV D+/R- SOT recipients who received 3 months of prophylaxis. Allograft rejection, over-immunosuppression and lack of CMV-specific immunity are factors that predispose patients to delayed-onset CMV disease. A recent randomized trial in CMV D+/R- kidney recipients demonstrates a significant reduction in the incidence of CMV disease when valganciclovir prophylaxis is extended to 200 days (compared with the standard 100 days) after transplantation; however, the safety and cost of this prolonged approach has yet to be assessed. In some studies, delayed-onset CMV disease has been significantly associated with allograft loss and mortality. In the vast majority of patients, CMV disease responds to treatment with intravenous ganciclovir. Recently, oral valganciclovir was demonstrated to have an efficacy that is comparable to intravenous ganciclovir in treating mild to moderate cases of CMV disease in SOT recipients. Reduction in the degree of immunosuppression should complement antiviral treatment of CMV disease. Although it remains rare, ganciclovir-resistant CMV disease is increasingly seen in clinical practice, potentially fostered by the prolonged use of antivirals in high-risk over-immunosuppressed transplant recipients. Treatment of drug-resistant CMV is currently non-standardized and may include foscarnet, cidofovir, CMV hyperimmune globulins or leflunomide. The investigational drug marivabir had the potential to treat ganciclovir-resistant CMV disease as it acts through a different mechanism. However, the recent phase III clinical trial in allogeneic bone marrow transplant recipients showed that maribavir was not significantly better than placebo for the prevention of CMV disease. Similarly, the preliminary data in a liver transplant population suggests that maribavir was inferior to oral ganciclovir for the prevention of CMV disease. This article reviews the recent data and other developments in the management of CMV infection after SOT.
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Affiliation(s)
- Albert J Eid
- Division of Infectious Diseases, University of Kansas Medical Center, Kansas City, Kansas, USA
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Zimmer RJ, Lee MS. Transplant Coronary Artery Disease. JACC Cardiovasc Interv 2010; 3:367-77. [DOI: 10.1016/j.jcin.2010.02.007] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Revised: 02/05/2010] [Accepted: 02/17/2010] [Indexed: 11/24/2022]
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Does Cytomegalovirus Serology Impact Outcome After Pediatric Heart Transplantation? J Heart Lung Transplant 2009; 28:1299-305. [DOI: 10.1016/j.healun.2009.07.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Revised: 07/06/2009] [Accepted: 07/28/2009] [Indexed: 11/21/2022] Open
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Zakliczynski M, Krynicka-Mazurek A, Konecka-Mrowka D, Nozynski J, Żegleń S, Przybylski R, Zembala M. Cytomegalovirus Infection Does Not Accelerate Microvasculopathy Development in Heart Transplant Recipients. Transplant Proc 2009; 41:3219-21. [DOI: 10.1016/j.transproceed.2009.07.068] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Britt W. Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. Curr Top Microbiol Immunol 2008; 325:417-70. [PMID: 18637519 DOI: 10.1007/978-3-540-77349-8_23] [Citation(s) in RCA: 234] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Infections with human cytomegalovirus (HCMV) are a major cause of morbidity and mortality in humans with acquired or developmental deficits in innate and adaptive immunity. In the normal immunocompetent host, symptoms rarely accompany acute infections, although prolonged virus shedding is frequent. Virus persistence is established in all infected individuals and appears to be maintained by both a chronic productive infections as well as latency with restricted viral gene expression. The contributions of the each of these mechanisms to the persistence of this virus in the individual is unknown but frequent virus shedding into the saliva and genitourinary tract likely accounts for the near universal incidence of infection in most populations in the world. The pathogenesis of disease associated with acute HCMV infection is most readily attributable to lytic virus replication and end organ damage either secondary to virus replication and cell death or from host immunological responses that target virus-infected cells. Antiviral agents limit the severity of disease associated with acute HCMV infections, suggesting a requirement for virus replication in clinical syndromes associated with acute infection. End organ disease secondary to unchecked virus replication can be observed in infants infected in utero, allograft recipients receiving potent immunosuppressive agents, and patients with HIV infections that exhibit a loss of adaptive immune function. In contrast, diseases associated with chronic or persistent infections appear in normal individuals and in the allografts of the transplant recipient. The manifestations of these infections appear related to chronic inflammation, but it is unclear if poorly controlled virus replication is necessary for the different phenotypic expressions of disease that are reported in these patients. Although the relationship between HCMV infection and chronic allograft rejection is well known, the mechanisms that account for the role of this virus in graft loss are not well understood. However, the capacity of this virus to persist in the midst of intense inflammation suggests that its persistence could serve as a trigger for the induction of host-vs-graft responses or alternatively host responses to HCMV could contribute to the inflammatory milieu characteristic of chronic allograft rejection.
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Affiliation(s)
- W Britt
- Department of Pediatrics, University of Alabama School of Medicine, Childrens Hospital, Harbor Bldg. 104, 1600 7th Ave. South Birmingham, AL 35233, USA.
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Association between a polymorphism in the IL-12p40 gene and cytomegalovirus reactivation after kidney transplantation. Transplantation 2008; 85:1406-11. [PMID: 18497679 DOI: 10.1097/tp.0b013e31816c7dc7] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is associated with a significant rate of morbidity after organ transplantation. The genetic factors influencing its occurrence have been little investigated. IL-12 plays a crucial role in anti-infectious immune responses, especially by stimulating IFNgamma production. An A-to-C single nucleotide polymorphism (SNP) within the 3'-untranslated region of the IL-12p40 gene has been characterized and was reported to be both functionally and clinically relevant. However, the impact of this single nucleotide polymorphism on events after organ transplantation has never been reported. METHODS In this study, we investigated the impact of the 3'-untranslated region polymorphism on the occurrence of CMV infection in 469 kidney recipients transplanted at the University Hospital of Tours between 1995 and 2005. The polymorphism was genotyped using the restriction fragment length polymorphism method and CMV infection was determined by pp65 antigenemia. RESULTS Multifactorial Cox regression analysis demonstrated that the presence of the C allele was an independent risk factor for CMV infection (OR=1.52, P=0.043), the risk being even higher when study was restricted to patients with positive CMV serological status before the graft and who did not receive any CMV prophylaxis (OR=1.88, P=0.028). CONCLUSIONS This study identified a new genetic risk factor for CMV reactivation after kidney transplantation. The results of our study suggest that C carriers might especially benefit from CMV prophylaxis.
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Reply. J Am Coll Cardiol 2008. [DOI: 10.1016/j.jacc.2008.02.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Cytomegalovirus disease in solid organ transplant recipients: advances lead to new challenges and opportunities. Curr Opin Organ Transplant 2007. [DOI: 10.1097/mot.0b013e3282f0d386] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Arora S, Jenum PA, Aukrust P, Rollag H, Andreassen AK, Simonsen S, Gude E, Fiane AE, Geiran O, Gullestad L. Pre-Transplant Toxoplasma gondiiSeropositivity Among Heart Transplant Recipients Is Associated With an Increased Risk of All-Cause and Cardiac Mortality. J Am Coll Cardiol 2007; 50:1967-72. [DOI: 10.1016/j.jacc.2007.07.068] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Revised: 06/22/2007] [Accepted: 07/30/2007] [Indexed: 11/26/2022]
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Zakliczyński M, Krynicka-Mazurek A, Pyka Ł, Trybunia D, Nadziakiewicz P, Przybylski R, Zembala M. The Influence of Cytomegalovirus Infection, Confirmed by pp65 Antigen Presence, on the Development of Cardiac Allograft Vasculopathy. Transplant Proc 2007; 39:2866-9. [DOI: 10.1016/j.transproceed.2007.09.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Rubin RH. The pathogenesis and clinical management of cytomegalovirus infection in the organ transplant recipient: the end of the 'silo hypothesis'. Curr Opin Infect Dis 2007; 20:399-407. [PMID: 17609600 DOI: 10.1097/qco.0b013e328285a358] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Cytomegalovirus infection is initiated when tumor necrosis factor binds to the cytomegalovirus receptors of latently infected cells, resulting in the reactivation of the virus and the production of clinical disease of two types: direct infection causing pneumonia, mononucleosis, colitis and other viral-related syndromes, and indirect infection in which an array of cytokines are released by the host that produce much the same effect as does the rejection process. RECENT FINDINGS These effects fall into three categories: allograft injury, an increase in superinfection with opportunistic pathogens and an increase in the incidence of B cell lymphoproliferative disease. Other factors that modulate the clinical impact of reactivated cytomegalovirus in the transplant patient include the past experience of the host with the virus (primary infection, donor seropositive and recipient seronegative), the degree of major histocompatibility complex mismatch, the viral burden and the amount of calcineurin inhibitor the patient receives. SUMMARY Optimal therapy for diagnosing, treating and preventing these indirect effects still remains to be defined; the direct effects, in contrast, are well managed with valganciclovir.
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Affiliation(s)
- Robert H Rubin
- Harvard Medical School, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, Division of Infectious Disease, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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