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Ossami Saidy RR, Kollar S, Czigany Z, Dittrich L, Raschzok N, Globke B, Schöning W, Öllinger R, Lurje G, Pratschke J, Eurich D, Uluk D. Detrimental impact of immunosuppressive burden on clinical course in patients with Cytomegalovirus infection after liver transplantation. Transpl Infect Dis 2024; 26:e14196. [PMID: 38010975 DOI: 10.1111/tid.14196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 10/14/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023]
Abstract
INTRODUCTION Cytomegalovirus (CMV)-infection and reactivation remain a relevant complication after liver transplantation (LT). The recipient and donor serum CMV-IgG-status has been established for risk stratification when choosing various pharmaceutical regimens for CMV-prophylaxis in the last two decades. However, factors influencing course of CMV-infection in LT remain largely unknown. In this study, the impact of immunosuppressive regimen was examined in a large cohort of patients. METHODS All patients that underwent primary LT between 2006 and 2018 at the Charité-Universitaetsmedizin, Berlin, were included. Clinical course as well as histological and laboratory findings of patients were analyzed our prospectively maintained database. Univariate and multivariate regression analysis for impact of variables on CMV-occurrence was conducted, and survival was examined using Kaplan-Meier analysis. RESULTS Overall, 867 patients were included in the final analysis. CMV-infection was diagnosed in 325 (37.5%) patients after transplantation. Significantly improved overall survival was observed in these patients (Log rank = 0.03). As shown by correlation and regression tree classification and regression tree analysis, the recipient/donor CMV-IgG-status with either positivity had the largest influence on CMV-occurrence. Analysis of immunosuppressive burden did not reveal statistical impact on CMV-infection, but statistically significant inverse correlation of cumulative tacrolimus trough levels and survival was found (Log rank < .001). Multivariate analysis confirmed these findings (p = .02). DISCUSSION CMV-infection remains of clinical importance after LT. Undergone CMV-infection of either recipient or donor requires prophylactic treatment. Additionally, we found a highly significant, dosage-dependent impact of immunosuppression (IS) on long-term outcomes for these patients, underlying the importance of minimization of IS in liver transplant recipients.
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Affiliation(s)
- Ramin Raul Ossami Saidy
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Stefanie Kollar
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Zoltan Czigany
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | - Luca Dittrich
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, Berlin, Germany
| | - Brigitta Globke
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Wenzel Schöning
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Robert Öllinger
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Dennis Eurich
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Deniz Uluk
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Title-Inflammatory Signaling Pathways in Allergic and Infection-Associated Lung Diseases. ALLERGIES 2022. [DOI: 10.3390/allergies2020006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Lung inflammation can be caused by pathogen infection alone or by allergic disease, leading to pneumonitis. Most of the allergens (antigens) that cause allergic lung diseases, including asthma and hypersensitivity pneumonitis (HP), are derived from microorganisms, such as bacteria, viruses, and fungi, but some inorganic materials, such as mercury, can also cause pneumonitis. Certain allergens, including food and pollen, can also cause acute allergic reactions and lead to lung inflammation in individuals predisposed to such reactions. Pattern recognition-associated and damage-associated signaling by these allergens can be critical in determining the type of hypersensitization and allergic disease, as well as the potential for fibrosis and irreversible lung damage. This review discusses the signs, symptoms, and etiology of allergic asthma, and HP. Furthermore, we review the immune response and signaling pathways involved in pneumonitis due to both microbial infection and allergic processes. We also discuss current and potential therapeutic interventions for infection-associated and allergic lung inflammation.
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Viehl E, Lichvar A, Chan C, Choi D. Incidence and risk factors for the development of cytomegalovirus viremia in a steroid sparing liver transplant center. Transpl Infect Dis 2022; 24:e13867. [PMID: 35604549 PMCID: PMC9541473 DOI: 10.1111/tid.13867] [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: 02/28/2022] [Revised: 04/14/2022] [Accepted: 05/12/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is a common opportunistic infection in patients after liver transplant (LT). Guidelines recommend 900mg daily of valganciclovir, however, valganciclovir commonly causes dose-dependent hematologic toxicities. Use of a low-dose valganciclovir (450mg) has been used to prevent these adverse effects, but the data regarding this dosing strategy is not as robust in a steroid sparing LT center. METHODS Retrospective chart review of adult LT recipients between January 1, 2008 and June 30, 2019. All patients received low-dose valganciclovir 450 mg PO daily for CMV prophylaxis. Primary outcome was the incidence of CMV viremia in LT recipients at 12 months post-LT. Secondary outcomes include time to CMV viremia, risk factors for the development of CMV viremia, and incidence of breakthrough CMV viremia while on valganciclovir prophylaxis. RESULTS A total of 266 patients were included. Overall, the majority were male (63.2%) and Caucasian (45.5%). The most common indication for transplant was decompensated cirrhosis (82%). The incidence of CMV at one year post-transplant was 7.9%. Independent risk factors included high risk status (OR 5.97, 95% CI 2.14-16.61, p = 0.001) as well as having an episode of rejection (OR 5.99, 95% CI 2.16-16.66, p = 0.001). CONCLUSION Low-dose valganciclovir can be effective in the prevention of CMV viremia in LT patients and may be a beneficial strategy for CMV prophylaxis in a steroid-sparing transplant center. Further studies may be needed to determine appropriate length of prophylaxis therapy for different risk groups. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Emily Viehl
- University of Illinois at Chicago College of Pharmacy
| | - Alicia Lichvar
- Center for Transplantation, University of California San Diego Health
| | - Christine Chan
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago College of Medicine
| | - David Choi
- Department of Pharmacy, Division of Gastroenterology and Hepatology, University of Chicago Medicine
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Singh N, Winston DJ, Razonable RR, Lyon GM, Silveira FP, Wagener MM, Limaye AP. Cost-effectiveness of Preemptive Therapy Versus Prophylaxis in a Randomized Clinical Trial for the Prevention of Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors. Clin Infect Dis 2021; 73:e2739-e2745. [PMID: 32712663 DOI: 10.1093/cid/ciaa1051] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R-) liver transplant recipients have not been assessed in the context of a randomized trial. METHODS A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R- liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy. RESULTS PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease). CONCLUSIONS PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R- liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease-associated costs due to delayed onset postprophylaxis disease in the prophylaxis group.
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Affiliation(s)
- Nina Singh
- University of Pittsburgh and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
| | - Drew J Winston
- University of California, Los Angeles Medical Center, Los Angeles, California, USA
| | | | | | - Fernanda P Silveira
- University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Marilyn M Wagener
- University of Pittsburgh and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
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Bixby AL, Fitzgerald L, Park JM, Kaul D, Tischer S. Comparison of standard versus low-dose valganciclovir regimens for cytomegalovirus prophylaxis in high-risk liver transplant recipients. Transpl Infect Dis 2021; 23:e13713. [PMID: 34428337 DOI: 10.1111/tid.13713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 07/23/2021] [Accepted: 07/31/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE The purpose of this study was to compare the safety and efficacy of two valganciclovir (VGCV) institutional dosing protocols for cytomegalovirus (CMV) prophylaxis in liver transplant (LT) recipients with CMV serotype donor +/recipient- (D+/R-). METHODS This was a single-center review of CMV D+/R- adult LT recipients who received VGCV 450 mg/day for 90 days (low-dose) or VGCV 900 mg/day for 180 days (standard-dose). The primary outcome was incidence of CMV disease at 1 year. Secondary outcomes included rates of CMV syndrome, end-organ disease, breakthrough infection, and resistance. Neutropenia, early discontinuation of VGCV, growth colony stimulating factors use (G-CSF), biopsy-proven rejection (BPAR), graft loss, and death at 1 year were analyzed. RESULTS Ninety-six CMV D+/R- LT recipients were included. Although no difference in CMV disease was observed (low-dose 26% vs. standard-dose 23%, p = 0.71), 75% of CMV infections in the low-dose group presented with end-organ disease. Ganciclovir (GCV) resistance was observed only in the low-dose group (n = 2). Significantly more patients in the standard-dose group developed neutropenia (low-dose 10% vs 60% standard-dose, p < 0.001). In the standard-dose group, 29% required early discontinuation of VGCV (vs. 5% in the low-dose group, p < 0.001), and 20% were treated with G-CSF. Both cohorts had similar rates of BPAR, graft loss, and death at 1 year. CONCLUSIONS VGCV 900 mg/day for 180 days had higher rates of hematologic adverse effects resulting in frequent treatment interruptions. However, the occurrence of two cases of GCV-resistant CMV disease raises concerns about routinely using low-dose VGCV prophylaxis.
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Affiliation(s)
- Alexandra L Bixby
- Department of Pharmacy Services, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Linda Fitzgerald
- Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Jeong M Park
- Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA.,Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA
| | - Daniel Kaul
- Department of Internal Medicine, Division of Infectious Diseases, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Sarah Tischer
- Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA
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Neuberger M, Sommerer C, Böhnisch S, Metzendorf N, Mehrabi A, Stremmel W, Gotthardt D, Zeier M, Weiss KH, Rupp C. Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients. Clin Res Hepatol Gastroenterol 2020; 44:543-550. [PMID: 31924555 DOI: 10.1016/j.clinre.2019.12.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients. AIM Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. METHODS This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival. RESULTS The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8μg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival. CONCLUSION MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.
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Affiliation(s)
- M Neuberger
- University Hospital Heidelberg, Internal Medicine IV, 69120 Heidelberg, Germany
| | - C Sommerer
- University Hospital Heidelberg, Division of Nephrology, 69120 Heidelberg, Germany
| | - S Böhnisch
- University Hospital Heidelberg, Division of Nephrology, 69120 Heidelberg, Germany
| | - N Metzendorf
- University Hospital Heidelberg, Division of Nephrology, 69120 Heidelberg, Germany
| | - A Mehrabi
- University of Heidelberg, Department of General, Visceral, and Transplantation Surgery, 69120 Heidelberg, Germany
| | - W Stremmel
- University Hospital Heidelberg, Internal Medicine IV, 69120 Heidelberg, Germany
| | - D Gotthardt
- University Hospital Heidelberg, Internal Medicine IV, 69120 Heidelberg, Germany
| | - M Zeier
- University Hospital Heidelberg, Division of Nephrology, 69120 Heidelberg, Germany
| | - K H Weiss
- University Hospital Heidelberg, Internal Medicine IV, 69120 Heidelberg, Germany
| | - C Rupp
- University Hospital Heidelberg, Internal Medicine IV, 69120 Heidelberg, Germany.
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Engelmann C, Sterneck M, Weiss KH, Templin S, Zopf S, Denk G, Eurich D, Pratschke J, Weiss J, Braun F, Welker MW, Zimmermann T, Knipper P, Nierhoff D, Lorf T, Jäckel E, Hau HM, Tsui TY, Perrakis A, Schlitt HJ, Herzer K, Tacke F. Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers. J Clin Med 2020; 9:2352. [PMID: 32717978 PMCID: PMC7465768 DOI: 10.3390/jcm9082352] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 12/22/2022] Open
Abstract
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3-6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.
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Affiliation(s)
- Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany;
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW32PF, UK
- Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Martina Sterneck
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
| | - Karl Heinz Weiss
- Department of Gastroenterology and Hepatology, University of Heidelberg, 69117 Heidelberg, Germany;
| | - Silke Templin
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, 72076 Tübingen, Germany;
| | - Steffen Zopf
- Department of Medicine 1, University of Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Gerald Denk
- Medical clinic and policlinic II, Campus Grosshadern, Ludwig Maximilians University (LMU), 80333 Munich, Germany;
- Transplantation Center Munich, University Hospital, 81377 LMU Munich, Germany
| | - Dennis Eurich
- Department of Surgery Campus Charité Mitte/Campus Virchow-Klinikum, 13353 Berlin, Germany; (D.E.); (J.P.)
| | - Johann Pratschke
- Department of Surgery Campus Charité Mitte/Campus Virchow-Klinikum, 13353 Berlin, Germany; (D.E.); (J.P.)
| | - Johannes Weiss
- Department of Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Felix Braun
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany;
| | - Martin-Walter Welker
- Department of Medicine I, University Hospital Frankfurt, 60590 Frankfurt, Germany;
| | - Tim Zimmermann
- Department of Medicine, Hepatology, University of Mainz, 55101 Mainz, Germany;
| | - Petra Knipper
- Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany;
| | - Dirk Nierhoff
- Department of Gastroenterology and Hepatology, University Hospital Köln, 50937 Köln, Germany;
| | - Thomas Lorf
- Clinic for General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany;
| | - Elmar Jäckel
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany;
| | - Hans-Michael Hau
- Department of Visceral, Transplantation, Thoracic, and Vascular Surgery, University Hospital Leipzig, 04103 Leipzig, Germany;
| | - Tung Yu Tsui
- Section of Oncological Surgery and Transplantation, Rostock University Medical Center, 18057 Rostock, Germany;
| | - Aristoteles Perrakis
- Department of General, Visceral, Vascular and Transplant Surgery, University Hospital Magdeburg, 39120 Magdeburg, Germany;
| | | | - Kerstin Herzer
- Knappschafts-Hospital Bad Neuenahr, Deutsche Rentenversicherung, Knappschaft-Bahn-See, 53474 Bad Neuenahr-Ahrweiler, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany;
- Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany
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Khan S, Sullivan T, Ali M, Dunn D, Patel G, Huprikar S. Low-dose valganciclovir for cytomegalovirus prophylaxis in intermediate-risk liver transplantation recipients. Liver Transpl 2018; 24:616-622. [PMID: 29500912 DOI: 10.1002/lt.25047] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 01/21/2018] [Accepted: 02/25/2018] [Indexed: 01/01/2023]
Abstract
Liver transplantation recipients (LTRs) who are seropositive for cytomegalovirus (CMV) (recipient seropositive [R+]) are at intermediate risk for CMV disease. A preventative strategy following transplant is considered standard of care. Current guidelines recommend high-dose valganciclovir (VGCV; 900 mg/day adjusted for renal function) for prophylaxis given limited data on the efficacy and safety of low-dose VGCV (450 mg/day adjusted for renal function). We describe our experience using low-dose VGCV prophylaxis for R+ LTRs at our institution. A single-center, retrospective study was conducted using a database of 364 LTRs over a 4-year period (2011-2014). Adult first-time R+ LTRs receiving low-dose VGCV prophylaxis were included. The primary endpoint was CMV disease at 1 year after transplant. Patients were compared with historical controls receiving high-dose VGCV prophylaxis. Secondary endpoints were biopsy-proven rejection and leukopenia on VGCV. With respect to leukopenia, patients receiving low-dose VGCV were compared with a group of D+R- patients from the database receiving high-dose VGCV. Univariate analyses were performed using chi-squared, Fisher's exact, and Wilcoxon rank sum tests. A total of 200 R+ LTRs met inclusion criteria. Median age was 60 years (interquartile range [IQR], 54-66 years), and 129 (65%) LTRs were male. Median Model for End-Stage Liver Disease score was 22 (IQR, 14-31), and 178 (89%) patients received deceased donor transplants. CMV disease occurred in only 9 (5%) patients, similar to rates in previous studies of LTRs receiving high-dose VGCV. Biopsy-proven rejection occurred in 18 (9%) patients. Patients received VGCV prophylaxis for a median of 3.4 (IQR, 3.1-4.3) months; 151 (76%) R+ LTRs receiving low-dose VGCV developed leukopenia. Premature VGCV discontinuation and granulocyte-colony stimulating factor use were infrequent and not significantly different between the 2 groups. In conclusion, low-dose VGCV was safe and effective for prevention of CMV disease in our cohort of 200 R+ LTR and should be considered as an option in future guidelines. Liver Transplantation 24 616-622 2018 AASLD.
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Affiliation(s)
- Salman Khan
- Division of Infectious Diseases, New York, NY
| | | | - Mohsin Ali
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - Dallas Dunn
- Division of Infectious Diseases, New York, NY
| | - Gopi Patel
- Division of Infectious Diseases, New York, NY
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Jorgenson MR, Descourouez JL, Leverson GE, McCreary EK, Lucey MR, Smith JA, Redfield RR. High-Dose Acyclovir for Cytomegalovirus Prophylaxis in Seropositive Abdominal Transplant Recipients. Ann Pharmacother 2017; 52:5-10. [DOI: 10.1177/1060028017728296] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Following abdominal solid organ transplant (aSOT), valganciclovir (VGC) is recommended for cytomegalovirus (CMV) prophylaxis. This agent is associated with efficacy concerns, toxicity, and emergence of ganciclovir resistance. Objective: To evaluate the incidence of high-dose acyclovir (HD-A) prophylaxis failure in seropositive aSOT recipients (R+). Methods: This was a retrospective, single-center study of R+ transplanted without lymphocyte-depleting induction between January 1, 2000, and June 30, 2013, discharged with 3 months of HD-A prophylaxis (800 mg 4 times daily). The primary outcome was incidence of prophylaxis failure. Secondary outcomes were incidence of biopsy-proven tissue-invasive disease and prophylaxis failure for each allograft subgroup. Results: A total of 1525 patients met inclusion criteria: 944 renal (RTX), 108 simultaneous pancreas-kidneys (SPK), 462 liver (LTX), and 11 pancreas (PTX) transplant recipients. The composite rate of HD-A prophylaxis failure was 7%; incidence of tissue-invasive disease was 0.4%. Failure rates were 4.5%, 6.1%, 11%, and 20% in the RTX, SPK, LTX, and PTX populations, respectively; tissue-invasive disease rates were 0.2%, 0%, 0.7%, and 10%. Failure occurred more frequently in the LTX and PTX populations ( P < 0.0001, HR = 2.6; P = 0.04 HR = 4.4). Incidence of tissue-invasive disease was minimal and not different in the RTX, LTX and SPK populations ( P = 0.34). When evaluating recipients of seronegative allografts (D−), the composite failure rate was 3.4% with no significant difference between allograft subgroups ( P = 0.45). Conclusion: HD-A may be a reasonable prophylaxis alternative for D−/R+ recipients, in the absence of lymphocyte-depleting induction, if low incidence viremia is tolerable. Future studies are needed to determine the long-term impact of CMV viremia in the setting of this prophylaxis approach.
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Affiliation(s)
| | | | - Glen E. Leverson
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Surgery, Madison, WI, USA
| | | | - Michael R. Lucey
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Madison, WI, USA
| | - Jeannina A. Smith
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Madison, WI, USA
| | - Robert R. Redfield
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Surgery, Madison, WI, USA
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Affiliation(s)
- Bobbi S Pritt
- Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
| | - Marie Christine Aubry
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Yadav SK, Saigal S, Choudhary NS, Saha S, Kumar N, Soin AS. Cytomegalovirus Infection in Liver Transplant Recipients: Current Approach to Diagnosis and Management. J Clin Exp Hepatol 2017; 7:144-151. [PMID: 28663679 PMCID: PMC5478971 DOI: 10.1016/j.jceh.2017.05.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 05/16/2017] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) infection is the most common viral infection in liver transplant recipients, affecting post-transplant patients and graft survival. Recent advances in diagnosis and management of CMV have led to marked reduction in incidence, severity, and its associated morbidity and mortality. CMV DNA assay is the most commonly used laboratory parameter to diagnose and monitor CMV infection. Current evidence suggests that both pre-emptive and universal prophylaxis approaches are equally justified in liver transplant recipients. Intravenous ganciclovir and oral valganciclovir are the most commonly used drugs for treatment of CMV disease. Most of the centre use valganciclovir prophylaxis for prevention of CMV disease in liver trasplant recipient. The aim of this article is to review the current standard of care for diagnosis and management of CMV disease in liver transplant recipients.
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Affiliation(s)
| | - Sanjiv Saigal
- Institute of Liver Transplantation and Regenerative Medicine and Dept of Microbiology, Medanta The Medicity, Gurugram, India
| | | | | | - Navin Kumar
- Institute of Liver Transplantation and Regenerative Medicine and Dept of Microbiology, Medanta The Medicity, Gurugram, India
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Abad CL, Razonable RR. Treatment of alpha and beta herpesvirus infections in solid organ transplant recipients. Expert Rev Anti Infect Ther 2016; 15:93-110. [PMID: 27911112 DOI: 10.1080/14787210.2017.1266253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Human herpesviruses frequently cause infections in solid organ transplant (SOT) recipients. Areas covered: We provide an overview of the clinical impact of alpha and beta herpesviruses and highlight the mechanisms of action, pharmacokinetics, clinical indications, and adverse effects of antiviral drugs for the management of herpes simplex virus, varicella zoster virus and cytomegalovirus. We comprehensively evaluated key clinical trials that led to drug approval, and served as the foundation for management guidelines. We further provide an update on investigational antiviral agents for alpha and beta herpesvirus infections after SOT. Expert commentary: The therapeutic armamentarium for herpes infections is limited by the emergence of drug resistance. There have been major efforts for discovery of new drugs against these viruses, but the results of early-phase clinical trials have been less than encouraging. We believe, however, that more antiviral drug options are needed given the adverse side effects associated with current antiviral agents, and the emergence of drug-resistant virus populations in SOT recipients. Likewise, optimized use and strategies are needed for existing and novel antiviral drugs against alpha and beta-herpesviruses in SOT recipients.
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Affiliation(s)
- C L Abad
- a Division of Infectious Diseases, Department of Medicine , Mayo Clinic , Rochester , MN , USA.,b Department of Medicine, Section of Infectious Diseases , University of the Philippines - Philippine General Hospital , Manila , Philippines
| | - R R Razonable
- a Division of Infectious Diseases, Department of Medicine , Mayo Clinic , Rochester , MN , USA.,c The William J. Von Liebig Center for Transplantation and Clinical Regeneration , Mayo Clinic , Rochester , MN , USA
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Fernández-Ruiz M, Silva J, López-Medrano F, Allende L, San Juan R, Cambra F, Justo I, Paz-Artal E, Jiménez C, Aguado J. Post-transplant monitoring of NK cell counts as a simple approach to predict the occurrence of opportunistic infection in liver transplant recipients. Transpl Infect Dis 2016; 18:552-65. [DOI: 10.1111/tid.12564] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 03/03/2016] [Accepted: 03/29/2016] [Indexed: 01/02/2023]
Affiliation(s)
- M. Fernández-Ruiz
- Unit of Infectious Diseases; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - J.T. Silva
- Unit of Infectious Diseases; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - F. López-Medrano
- Unit of Infectious Diseases; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - L.M. Allende
- Department of Immunology; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - R. San Juan
- Unit of Infectious Diseases; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - F. Cambra
- Department of Abdominal Organ Transplantation and General and Digestive Surgery; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - I. Justo
- Department of Abdominal Organ Transplantation and General and Digestive Surgery; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - E. Paz-Artal
- Department of Immunology; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - C. Jiménez
- Department of Abdominal Organ Transplantation and General and Digestive Surgery; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
| | - J.M. Aguado
- Unit of Infectious Diseases; Hospital Universitario “12 de Octubre”; Instituto de Investigación Hospital “12 de Octubre” (i+12); School of Medicine; Universidad Complutense; Madrid Spain
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14
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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: 64] [Impact Index Per Article: 7.1] [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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Mitchell SL, Kajon AE, Kaplan SL, Kim J, Cárdenas AM. An unusual case of disseminated adenovirus infection in a cystic fibrosis, liver transplant patient. J Clin Virol 2016; 81:64-7. [PMID: 27331823 DOI: 10.1016/j.jcv.2016.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 05/20/2016] [Accepted: 05/26/2016] [Indexed: 11/25/2022]
Affiliation(s)
- Stephanie L Mitchell
- Department of Pathology and Laboratory Medicine, The Perelman School of Medicine, Philadelphia, PA, United States
| | - Adriana E Kajon
- Lovelace Respiratory Research Institute, Albuquerque, NM, United States
| | - Summer L Kaplan
- Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jason Kim
- Department of Pediatrics, The Perelman School of Medicine, Philadelphia, PA, United States; Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Ana María Cárdenas
- Department of Pathology and Laboratory Medicine, The Perelman School of Medicine, Philadelphia, PA, United States; Infectious Diseases Diagnostics Laboratory, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
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Oral Valganciclovir as a Preemptive Treatment for Cytomegalovirus (CMV) Infection in CMV-Seropositive Liver Transplant Recipients. PLoS One 2015; 10:e0123554. [PMID: 25942443 PMCID: PMC4420490 DOI: 10.1371/journal.pone.0123554] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 03/05/2015] [Indexed: 12/13/2022] Open
Abstract
Objectives Cytomegalovirus (CMV) infections in liver transplant recipients are common and result in significant morbidity and mortality. Intravenous ganciclovir or oral valganciclovir are the standard treatment for CMV infection. The present study investigates the efficacy of oral valganciclovir in CMV infection as a preemptive treatment after liver transplantation. Methods Between 2012 and 2013, 161 patients underwent liver transplantation at Samsung Medical Center. All patients received tacrolimus, steroids, and mycophenolate mofetil. Patients with CMV infection were administered oral valganciclovir (VGCV) 900mg/day daily or intravenous ganciclovir (GCV) 5mg/kg twice daily as preemptive treatment. Stable liver transplant recipients received VGCV. Results Eighty-three patients (51.6%) received antiviral therapy as a preemptive treatment because of CMV infection. The model for end-stage liver disease (MELD) score and the proportions of Child-Pugh class C, hepatorenal syndrome, and deceased donor liver transplantation in the CMV infection group were higher than in the no CMV infection group. Sixty-one patients received GCV and 22 patients received VGCV. The MELD scores in the GCV group were higher than in the VGCV group, but there were no statistical differences in the pretransplant variables between the two groups. AST, ALT, and total bilirubin levels in the GCV group were higher than in the VGCV group when CMV infection occurred. The incidences of recurrent CMV infection in the GCV and VGCV groups were 14.8% and 4.5%, respectively (P=0.277). Conclusion Oral valganciclovir is feasible as a preemptive treatment for CMV infection in liver transplant recipients with stable graft function.
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McKeen JT, Tsapepas DS, Li H, Anamisis A, Martin ST. Acyclovir versus Valganciclovir for Preventing Cytomegalovirus Infection in Intermediate-Risk Liver Transplant Recipients. Prog Transplant 2015; 25:39-44. [DOI: 10.7182/pit2015558] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Context Cytomegalovirus (CMV) is an opportunistic infection that causes profound morbidity and mortality after orthotopic liver transplant (OLT). The CMV immunoglobulin G serostatuses of donors and recipients are the main factors influencing risk for development of CMV infection after transplant. Objective To compare acyclovir and valganciclovir for preventing CMV infection after OLT. Design, Setting, and Patients Retrospective assessment of adult OLT recipients at intermediate risk for CMV infection at New York Presbyterian Hospital. Intervention All patients received ganciclovir 5 mg/kg intravenously every 12 hours or valganciclovir 900 mg orally every 12 hours for 7 days after transplant. On postoperative day 8, patients received antiviral prophylaxis according to risk stratification: acyclovir 800 mg orally 3 times daily in donor seronegative/recipient seropositive (D-/R+) patients or valganciclovir 900 mg orally once daily in donor seropositive/recipient seropositive (D+/R+) patients. Main Outcome Measure Composite incidence of CMV infection, syndrome, or tissue-invasive disease. Results Of 275 OLT recipients, 89 were at intermediate risk for CMV infection (29 D−/R+, 60 D+/R+). CMV infection, syndrome, or tissue-invasive disease occurred in 1 patient (3%) in the D−/R+ group and 5 patients (8%) in the D+/R+ group ( P=.66). One patient (3%) in the D−/R+ group had a CMV infection develop. Five D+/R+ recipients (8%) had CMV infection; 3 of them had CMV syndrome (5%), 1 had CMV hepatitis (1.6%), and the other had CMV esophagitis (1.6%); all events occurred after prophylaxis was discontinued. The rates of CMV infection were similar in D−/R+ patients treated with acyclovir and D+/R+ patients receiving valganciclovir. This risk-stratified approach to viral prophylaxis after OLT resulted in an acceptable rate of CMV infection in D−/R+ recipients and may avoid the costs and adverse effects associated with valganciclovir therapy.
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Affiliation(s)
- Jaclyn T. McKeen
- Hackensack University Medical Center, Hackensack, New Jersey (JTM), New York-Presbyterian Hospital, Columbia University Medical Center, New York (DST, HL, AA), Hartford Hospital, Hartford, Connecticut (STM)
| | - Demetra S. Tsapepas
- Hackensack University Medical Center, Hackensack, New Jersey (JTM), New York-Presbyterian Hospital, Columbia University Medical Center, New York (DST, HL, AA), Hartford Hospital, Hartford, Connecticut (STM)
| | - Hanlin Li
- Hackensack University Medical Center, Hackensack, New Jersey (JTM), New York-Presbyterian Hospital, Columbia University Medical Center, New York (DST, HL, AA), Hartford Hospital, Hartford, Connecticut (STM)
| | - Anastasia Anamisis
- Hackensack University Medical Center, Hackensack, New Jersey (JTM), New York-Presbyterian Hospital, Columbia University Medical Center, New York (DST, HL, AA), Hartford Hospital, Hartford, Connecticut (STM)
| | - Spencer T. Martin
- Hackensack University Medical Center, Hackensack, New Jersey (JTM), New York-Presbyterian Hospital, Columbia University Medical Center, New York (DST, HL, AA), Hartford Hospital, Hartford, Connecticut (STM)
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Mumtaz K, Faisal N, Husain S, Morillo A, Renner EL, Shah PS. Universal prophylaxis or preemptive strategy for cytomegalovirus disease after liver transplantation: a systematic review and meta-analysis. Am J Transplant 2015; 15:472-81. [PMID: 25522141 DOI: 10.1111/ajt.13044] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 09/24/2014] [Accepted: 09/28/2014] [Indexed: 02/06/2023]
Abstract
We systematically reviewed and meta-analyze the efficacy of universal prophylaxis (UP) and preemptive (PE) strategies (using ganciclovir or valganciclovir) in preventing cytomegalovirus (CMV) disease (CMD) among liver transplant recipients (LTRs). We performed an electronic search of MEDLINE, EMBASE and the Cochrane Database till December 2013. Studies that assessed UP or PE for preventing CMD in LTRs were included. The risk of bias was assessed using the Newcastle-Ottawa scale. The primary outcome was CMD, secondary outcomes being acute cellular rejection (ACR), graft loss (GL) and mortality. Due to the heterogeneity of comparative studies, an indirect comparison was performed. Pooled incidence rates with 95% confidence interval (CI) are calculated for each outcome using a random-effects model. Thirty-two studies involving 2456 LTRs were included. The majority of the studies were of low risk of bias. Irrespective of donor/recipient CMV sero-status, CMD was 10% with UP (95% CI: 6-14; I(2) = 87%; 16 studies, n = 1581) and 7% with PE (95% CI: 3-10; I(2) = 84%; 16 studies, n = 875) (mean difference 2.6; 95% CI: -3.25 to 8.45, p = 0.34). Likewise, ACR and mortality were similar with the two strategies. However, GL was significantly lower in the UP group, regardless of donor/recipient sero-status. In indirect comparison, the incidence of CMD, ACR and mortality in LTRs were similar with two strategies. Trials comparing the two strategies directly are needed.
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Affiliation(s)
- K Mumtaz
- Wexner Medical Center, Gastroenterology, Hepatology and Nutrition Division, The Ohio State University, Columbus, OH
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Beam E, Dioverti V, Razonable RR. Emerging cytomegalovirus management strategies after solid organ transplantation: challenges and opportunities. Curr Infect Dis Rep 2014; 16:419. [PMID: 24986636 DOI: 10.1007/s11908-014-0419-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cytomegalovirus (CMV) remains as one of the most common pathogens after solid organ transplantation (SOT). During the past year, management guidelines were updated, and numerous studies were published-all collectively emphasizing the ongoing efforts to improve management of CMV after SOT. Improvement in laboratory diagnostics was aided by the WHO international calibration standard for nucleic acid testing, which allows for meaningful comparison of viral load values among laboratories. The potential translation of methods for assessing CMV-specific cellular immunity could provide tools for CMV risk assessment and management. Efforts continue to optimize antiviral strategies for CMV disease prevention and treatment. CMV vaccines continue to be tested in various stages of clinical trials. Novel anti-CMV drugs are being developed, including agents that have been used as compassionate therapy for treatment of drug-resistant CMV. In this article, the authors review recent developments on CMV and discuss their implications in CMV management after transplantation.
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Affiliation(s)
- E Beam
- Division of Infectious Diseases, Department of Medicine, and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA
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Marcelin JR, Beam E, Razonable RR. Cytomegalovirus infection in liver transplant recipients: Updates on clinical management. World J Gastroenterol 2014; 20:10658-10667. [PMID: 25152570 PMCID: PMC4138447 DOI: 10.3748/wjg.v20.i31.10658] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/24/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) infection is a common complication after liver transplantation, and it is associated with multiple direct and indirect effects. Management of CMV infection and disease has evolved over the years, and clinical guidelines have been recently updated. Universal antiviral prophylaxis and a pre-emptive treatment strategy are options for prevention. A currently-recruiting randomized clinical trial is comparing the efficacy and safety of the two prevention strategies in the highest risk D+R- liver recipients. Drug-resistant CMV infection remains uncommon but is now increasing in incidence. This highlights the currently limited therapeutic options, and the need for novel drug discoveries. Immunotherapy and antiviral drugs with novel mechanisms of action are being investigated, including letermovir (AIC246) and brincidofovir (CMX001). This article reviews the current state of CMV management after liver transplantation, including the updated practice guidelines, and summarizes the data on investigational drugs and vaccines in clinical development.
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Bruminhent J, Razonable RR. Management of cytomegalovirus infection and disease in liver transplant recipients. World J Hepatol 2014; 6:370-383. [PMID: 25018848 PMCID: PMC4081612 DOI: 10.4254/wjh.v6.i6.370] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/23/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and such occurrence of late-onset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach (antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation.
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Fagiuoli S, Colli A, Bruno R, Craxì A, Gaeta GB, Grossi P, Mondelli MU, Puoti M, Sagnelli E, Stefani S, Toniutto P, Burra P. Management of infections pre- and post-liver transplantation: report of an AISF consensus conference. J Hepatol 2014; 60:1075-89. [PMID: 24384327 DOI: 10.1016/j.jhep.2013.12.021] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/18/2013] [Accepted: 12/19/2013] [Indexed: 02/06/2023]
Abstract
The burden of infectious diseases both before and after liver transplantation is clearly attributable to the dysfunction of defensive mechanisms of the host, both as a result of cirrhosis, as well as the use of immunosuppressive agents. The present document represents the recommendations of an expert panel commended by the Italian Association for the Study of the Liver (AISF), on the prevention and management of infectious complications excluding hepatitis B, D, C, and HIV in the setting of liver transplantation. Due to a decreased response to vaccinations in cirrhosis as well as within the first six months after transplantation, the best timing for immunization is likely before transplant and early in the course of disease. Before transplantation, a vaccination panel including inactivated as well as live attenuated vaccines is recommended, while oral polio vaccine, Calmette-Guerin's bacillus, and Smallpox are contraindicated, whereas after transplantation, live attenuated vaccines are contraindicated. Before transplant, screening protocols should be divided into different levels according to the likelihood of infection, in order to reduce costs for the National Health Service. Recommended preoperative and postoperative prophylaxis varies according to the pathologic agent to which it is directed (bacterial vs. viral vs. fungal). Timing after transplantation greatly determines the most likely agent involved in post-transplant infections, and specific high-risk categories of patients have been identified that warrant closer surveillance. Clearly, specifically targeted treatment protocols are needed upon diagnosis of infections in both the pre- as well as the post-transplant scenarios, not without considering local microbiology and resistance patterns.
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Affiliation(s)
- Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
| | | | - Raffaele Bruno
- Department of Infectious Diseases, IRCCS San Matteo, University of Pavia, Pavia, Italy
| | - Antonio Craxì
- Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Italy
| | - Giovanni Battista Gaeta
- Infectious Diseases, Department of Internal and Experimental Medicine, Second University of Naples, Italy
| | - Paolo Grossi
- Infectious & Tropical Diseases Unit, Department of Surgical & Morphological Sciences, Insubria University, Varese, Italy
| | - Mario U Mondelli
- Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine, University of Pavia, Italy
| | - Massimo Puoti
- Infectious Diseases Department, Niguarda Cà Granda Hospital, Milano, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Preventive Medicine, Second University of Naples, Italy
| | - Stefania Stefani
- Department of Bio-Medical Sciences, Section of Microbiology, University of Catania, Italy
| | - Pierluigi Toniutto
- Department of Medical Sciences, Experimental and Clinical, Medical Liver Transplant Section, Internal Medicine, University of Udine, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
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24
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Ramsay ID, Lestner JM, O’Sullivan CP, Cruz AL, Li HK, Barker CI. Antiviral Drugs. SIDE EFFECTS OF DRUGS ANNUAL 2014:401-443. [DOI: 10.1016/b978-0-444-63407-8.00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Kowalsky S, Arnon R, Posada R. Prevention of cytomegalovirus following solid organ transplantation: a literature review. Pediatr Transplant 2013; 17:499-509. [PMID: 23890075 DOI: 10.1111/petr.12118] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/29/2013] [Indexed: 02/06/2023]
Abstract
CMV is the most common opportunistic infection affecting SOT recipients. Although current strategies to prevent both CMV infection and disease have been effective, CMV related complications continue to occur, particularly late-onset CMV disease. This literature review article examines the benefits and disadvantages of different prevention modalities, and presents emerging strategies to better prevent CMV in organ transplant recipients.
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Affiliation(s)
- Shanna Kowalsky
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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26
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Fallatah SM, Marquez MA, Bazerbachi F, Schiff JR, Cattral MS, McGilvray ID, Norgate A, Selzner M, Rotstein C, Husain S. Cytomegalovirus infection post-pancreas-kidney transplantation--results of antiviral prophylaxis in high-risk patients. Clin Transplant 2013; 27:503-9. [PMID: 23731387 DOI: 10.1111/ctr.12138] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is a major pathogen affecting solid organ transplant (SOT) recipients. Prophylactic strategies have decreased the rate of CMV infection/disease among SOT. However, data on the effect of current prophylactic strategies for simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplant remain limited. We report our experience of CMV prophylaxis in SPK/PAK recipients. METHODS A total of 130 post-SPK/PAK patients were analyzed retrospectively for the rate of CMV and the risk factors associated with the acquisition of CMV. All patients received antiviral prophylaxis. The follow-up period was one yr post-transplant or until death. RESULTS The rate of CMV post-SPK/PAK transplant was 24%, 44%, and 8.2% among the whole cohort, the D+/R- and the R+ groups, respectively. Median time of prophylaxis was 49 (0-254) d. In the whole cohort, risk factors for CMV infection/diseases were D+/R- CMV status (odds ratio [OR] = 16.075), preceding non-CMV (infection caused by bacteria or fungi and other viruses) infection (OR = 6.362) and the duration of prophylaxis (OR = 0.984). Among the CMV D+/R- group, non-CMV infection was the only risk factor for CMV disease (OR = 10.7). CONCLUSIONS Forty-four per cent (25/57) of the D+/R- recipients developed CMV infection/disease despite CMV prophylaxis. Current CMV prophylaxis failed to prevent CMV infection/disease in this group of patients.
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Affiliation(s)
- Samira M Fallatah
- Division of Infectious Diseases, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
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