Review
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Jul 29, 2020; 10(7): 183-190
Published online Jul 29, 2020. doi: 10.5500/wjt.v10.i7.183
Cytomegalovirus infection after liver transplantation
Blanca C Lizaola-Mayo, Eduardo A Rodriguez
Blanca C Lizaola-Mayo, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ 85259, United States
Eduardo A Rodriguez, Division of Gastroenterology, Hepatology & Nutrition, University of Utah, Salt Lake City, UT 84132, United States
ORCID number: Blanca C Lizaola-Mayo (0000-0003-0130-0091); Eduardo A Rodriguez (0000-0001-9684-8273).
Author contributions: Lizaola-Mayo BC and Rodriguez EA wrote the paper.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Eduardo A Rodriguez, MD, Assistant Professor, Division of Gastroenterology, Hepatology & Nutrition, University of Utah, 30 N 1900 E, Room 4R118, Salt Lake City, UT 84132, United States. eduardo.rodriguez@hsc.utah.edu
Received: March 24, 2020
Peer-review started: March 24, 2020
First decision: April 22, 2020
Revised: May 28, 2020
Accepted: July 1, 2020
Article in press: July 1, 2020
Published online: July 29, 2020

Abstract

Human cytomegalovirus (CMV) represents the most common opportunistic infection in liver transplant recipients. CMV infections in post liver transplant patients cause significant morbidity and mortality, directly affecting post-transplant outcomes. This review will provide the framework for the surveillance, diagnosis, prophylaxis and treatment of CMV in the liver transplant population.

Key Words: Cytomegalovirus, Liver transplant, Immunosuppression, Serostatus

Core tip: Cytomegalovirus (CMV) is the most common infection in the liver transplant population directly affecting posttransplant outcomes through its direct and indirect effects. The donor and recipient’s CMV serostatus represent the most important factor to determine CMV posttransplant risk, and the need for prophylaxis. Herein, we discuss and summarize the most current CMV preventive, diagnostic, and therapeutic strategies in this vulnerable cohort of patients.



INTRODUCTION

Cytomegalovirus (CMV) or human herpes virus 5 (HHV 5) is a member of the Herpesviridae family. It is a double stranded DNA virus that gives the appearance of intranuclear inclusions in infected cells[1]. The primary infection tends to happen during the first 2 decades of life[2-4]. In immunocompetent patients, the infection can be asymptomatic or self-limited. After the primary infection, the virus remains latent in the body, serving as a reservoir[5]. Reactivation and transmission are higher in susceptible individuals, either due to acquired immunodeficiency syndrome (AIDS) or secondary to induced immunosuppression like in the case of liver transplant recipients[5]. In developed countries, the seroprevalence of CMV is around 50%, and in developing countries this percentage increases up to 97%[1,3,6]. CMV is the most common opportunistic infection in liver transplant recipients, directly affecting graft survival and patient mortality[7,8]. Despite the development of diagnostic, therapeutic and prophylactic measures, up to 29% of liver transplant recipients develop CMV disease jeopardizing posttransplant outcomes[9-11].

INFECTION PATHOPHYSIOLOGY

Among adults, transmission occurs through exposure of bodily fluids and tissue including saliva, tears, blood and transplanted grafts[12]. The primary infection happens in mucosal epithelial cells and the virus disseminates through circulating CD14+ monocytes[13]. After the primary infection, the virus remains latent in lymphoid and myeloid cells. In liver transplant recipients without prophylaxis, CMV infection tends to occur within the first three months after transplantation[4]. CMV reactivation or infection is directly affected by the serologic status of the donor and recipient, degree of immunosuppression and prophylaxis[14]. CMV has a predilection to attack the transplanted allograft amongst other organs – causing hepatitis in liver recipients (mainly infecting hepatocytes and macrophages)[15]. It is unclear why CMV tends to attack the transplanted graft, however, it is believed that this occurs as the organ serves as a reservoir that harbors latent CMV which is undetected by the impaired immune system[9]. Following transplantation, CMV infection reactivates from latency, starts viral replication mainly in lymphoid-rich organs, and ultimately disseminates through the blood stream to other organs[16].

RISK FACTORS

The biggest risk factor in liver transplant recipients that increases the likelihood of developing CMV disease is the recipient’s CMV-seronegative status[17]. CMV infection has a reported incidence of 78%-88% in seronegative recipients (R-) obtaining a seropositive organ (D+) without prophylaxis. This percentage decreases to 13% in seronegative recipients from seronegative donors[8,18]. Immunosuppressant drugs block T-cell function and cause severe lymphopenia, increasing the risk of CMV after liver transplantation[19,20]. A higher risk has been seen in patients receiving elevated doses of maintenance immunosuppression[21]. The use of lymphocyte-depleting agents like alemtuzuman, muromonab-CD3 and anti-thymocyte globulins has been identified as a risk as well[22,23]. In contrast, the lowest risk has been seen when utilizing sirolimus and everolimus (mTOR inhibitors)[21,24]. The use of lymphocyte-depleting antibodies to treat allograft rejection, has been associated with an increased risk for CMV infection too[25]. The risk of CMV disease in liver transplant recipients is higher than in kidney recipients and lower than lung, small intestine and simultaneous heart-lung recipients[26-29]. Other risk factors include: donor and/or recipient advanced age, HLA mismatch, immediate graft rejection by itself, impaired humoral immunity and coinfection with other herpes viruses (HSV 6 and 7)[10,30,31].

SEROLOGIC STATUS

Prior to transplantation, all candidates and donors must be tested for CMV using CMV-IgG serology[7]. The presence of CMV IgG antibodies through previous exposure catalogs recipients and donors as seropositive[7]. Recipients who are CMV seronegative have the highest risk of CMV infection when receiving a CMV-positive organ (D+/R-) with rates up to 88% without prophylaxis[32]. A moderate risk is seen in seropositive recipients receiving a seropositive organ (D+/R+)[33]. The lowest risk is in seronegative recipients receiving seronegative organs (D-/R-). This last group may still acquire the infection from person to person or from transfused blood products[17]. Amongst CMV-seropositive recipients, the risk is higher when receiving a CMV+ organ, likely due to superinfection (Table 1).

Table 1 Risk of cytomegalovirus infection based on donor and recipient serostatus.
DonorRecipientRiskRecommended prophylaxis length
PositiveNegativeHighest6 months
PositivePositiveHigher3 months
NegativePositiveModerate3 months
NegativeNegativeLowNot recommended
CLINICAL MANIFESTATIONS

Based on the recently published American Society of Transplantation CMV in solid organ transplant recipient guidelines[7], it is important to standardize disease definitions: CMV infection is the presence of CMV replication regardless of symptomatology. CMV replication can be detected by nucleic acid testing (NAT), antigen testing or viral culture[12]. CMV disease is defined as CMV infection accompanied by clinical signs and symptoms. Asymptomatic CMV infection is CMV replication without symptomatology[12]. CMV syndrome is characterized by the detection of CMV in blood plus at least two of the following: Fever ≥ 38 °C for at least 48 hours, new or increased malaise or fatigue, leukopenia or neutropenia on two separate measurements, 5% atypical lymphocytes, thrombocytopenia and transaminitis three times the upper limit of normal (ULN)[7,9].

Most CMV cases (60%) in post liver transplant patients present as a mononucleosis-like syndrome (fevers, myalgias, arthralgias and malaise) along with hematologic abnormalities and hepatitis[34]. CMV hepatitis normally presents with jaundice, mixed hepatocellular and cholestatic elevation of liver chemistries (within 3 × ULN), and documented viral presence in the liver tissue[35]. This presentation, may be confused with allograft rejection or other causes of hepatitis[36]. Few cases of fulminant and granulomatous hepatitis in the setting of CMV infections have been described as well[37-39]. Gastrointestinal CMV disease is also common in liver transplant recipients; it is defined as the presence of upper and or lower gastrointestinal (GI) symptoms with documented CMV in tissue. Serum presence of CMV alone is not sufficient for diagnosis of CMV GI disease. It tends to manifest with odynophagia, dysphagia, nausea, vomiting, epigastric pain, bloating, diarrhea and hematochezia[40]. The colon is reportedly the most common GI site to be involved (94% of cases)[41-43].

CMV infection has been related with a four-fold increased risk of acute and chronic allograft rejection through the potentiation of alloantigens[44]. CMV also has immunosuppressive effects through the impairment of CD4 T cells and macrophages - it also decreases the levels of interleukin 1 and 2 and increases the levels of interferon alpha. All these indirect effects increase the risk of invasive fungal infections, bacteremia, EBV-associated posttransplant lymphoproliferative disease and cardiovascular disease[44,45]. Thrombosis of the graft has also been described due to the proinflammatory state that CMV infection causes[25,31]. It may even facilitate reactivation and replication of hepatitis C virus[46].

DIAGNOSIS

Serologic diagnosis of the donor and recipient is paramount due to its significant implications in posttransplant outcomes. In the solid organ transplantation cohort, IgM and IgG antibodies have a sensitivity of 90%, antigenemia 80% and CMV PCR of 84% to 100%[47]. PCR is the preferred CMV detection method in liver transplant patients[48].

The diagnosis of CMV disease in liver transplant recipients is made through the identification of clinical manifestations including fever, fatigue, malaise, leukopenia, thrombocytopenia and elevation of liver enzymes plus identification of CMV viremia and detection of the virus in target organs[12]. Liver biopsy may be warranted due to the increased risk for allograft rejection in the setting of CMV infection[48]. The main diagnostic tests utilized are viral culture in cells, detection of viral nucleic acid through PCR and identification of viral proteins through antigenemia essays[16]. Urine CMV detection has a poor correlation with CMV disease as it usually represents viral shedding, however it has been identified as one of the first methods to identify CMV replication in CMV seronegative recipients from positive donors[49]. Whole blood has been identified to be superior over plasma, peripheral blood leukocytes and peripheral blood mononuclear cells for the quantification of CMV DNA by PCR[50].

As mentioned before, the gastrointestinal tract is the second most common target for CMV infection in the liver transplant population. Endoscopic evaluation of the large intestine with terminal ileum intubation with biopsies is recommended as isolated ileal involvement in the setting of invasive gastrointestinal CMV infection has been reported[51,52]. Endoscopic findings vary from mucosal inflammation to severe ulcerations with the characteristic diagnostic inclusion bodies seen from biopsies taken from the ulcer base[40].

THERAPY

Due to its direct and indirect effects, CMV infection prevention is a major strategy in post liver transplant patients. With the use of prophylaxis against CMV, there has been a reported reduction of CMV infection up to 80% during the first 90 days after transplant[53]. Amongst D+/R- liver transplant patients, CMV prophylaxis has shown to be superior to preemptive therapy[54,55]. CMV prophylaxis should be started within the first 10 days after transplant[7].

Prophylaxis

Oral Valganciclovir and intravenous (IV) Ganciclovir are the antiviral drugs used for CMV prophylaxis[56]. A novel viral terminase inhibitor called Letenovir has been recently approved as a prophylactic drug in hematopoietic stem cell transplantation and is under a clinical trial in kidney transplant CMV D+/R- patients (ClinicalTrials.gov NCT03443869)[57]. To our knowledge, this drug has not been studied in the liver transplant cohort. Studies have shown comparable safety and efficacy between ganciclovir and valganciclovir[58]. Valganciclovir has not been approved for CMV prophylaxis by the U.S. Food and Drug Administration due to a subgroup analysis revealing higher rates of tissue invasive CMV disease in liver transplant patients treated with this drug[56]. Regardless, as an oral drug with improved bioavailability, Valganciclovir is still the preferred prophylactic drug over IV Ganciclovir in liver recipients[59]. The recommended valganciclovir dose is 900 mg per day which needs to be adjusted in patients with kidney disease[60]. The ideal duration in high-risk patients (D+/R-) has not been specifically studied in liver transplant patients, however due to the increased risk of postprophylaxis delayed-CMV disease seen during the first six months, and the decreased rate of CMV infection in a kidney transplant population receiving CMV prophylaxis; most transplant centers apply the prophylaxis for six months[56,60]. In CMV R+ patients, prophylaxis is recommended to last 3 months and in D-/R- prophylaxis is not indicated. After conclusion of CMV prophylaxis, it is important to monitor for postprophylaxis delayed-onset CMV disease weekly for three months[7].

Preemptive therapy

Preemptive therapy should be started as soon as CMV viremia (> threefold increase in serum CMV PCR) is identified[61]. Oral valganciclovir 900 mg twice a day to be adjusted for renal impairment or IV ganciclovir 5 mg/kg twice a day have a similar reported treatment efficacy of up to 85% in posttransplant patients[58] (Table 2). Treatment is advised to be continued until there is a documented negative quantitative CMV PCR. Due to its high sensitivity it is not necessary to confirm two consecutive negative tests anymore[48,62].

Table 2 Antiviral drugs for cytomegalovirus prophylaxis and treatment in liver transplant patients.
DrugRouteProphylaxis doseTreatment doseSide effects
GanciclovirIV5 mg/kg daily5 mg/kg twice a dayBone marrow suppression
ValganciclovirOral900 mg once a day900 mg twice a dayLeukopenia
FoscarnetIV-60 mg/kg every 8 h or 90 mg/kg every 12 hNephrotoxicity
CidofovirIV-5 mg/kg weekly × 2, then every 2 wkNephrotoxicity
CMV disease therapy

For stablished CMV disease, IV ganciclovir (5 mg/kg twice a day) is recommended for severe disease. For mild to moderate disease, oral valganciclovir 900 mg twice a day (renally-dosed) has shown to be equally effective to ganciclovir[58]. Foscarnet and cidofovir are considered second line drugs due to its nephrotoxic effects[63]. Therapy should be given for at least 2 weeks and discontinuation is based upon virological clearance and resolution of symptomatology[62,64]. Persistent viremia after therapy and extensive involvement of the gastrointestinal tract have been identified as risk factors for CMV relapse[65]. CMV seroconversion, viral load, treatment duration, maintenance therapy and endoscopic findings at the end of therapy are not significantly associated with CMV relapse[66].

CMV resistance to antiviral drugs is an emerging problem. Resistance happens through mutations of the viral DNA polymerase UL54 and the thymidine kinase UL97[67]. The incidence of CMV resistance in liver transplant patients is not well defined, however it is believed that in solid organ transplants in general it is around 7% in high risk patients[68,69]. When ganciclovir and valganciclovir are shown to be ineffective due to resistance, patients should be treated with combination therapy, foscarnet and cidofovir or experimental treatments[70].

CONCLUSION

CMV is the most common opportunistic infection in liver transplant patients. Its direct and indirect effects directly impact post liver transplant outcomes and patient mortality. Pre-transplant donor and recipient serological identification are key to determine posttransplant CMV risk and prophylaxis need. Current therapies have shown to be effective, however ongoing trials are focusing on prevention through vaccines and novel drugs for resistant cases.

Footnotes

Manuscript source: Invited manuscript

Corresponding Author's Membership in Professional Societies: American Association for the Study of Liver Diseases; American College of Gastroenterology; and American Society of Gastrointestinal Endoscopy.

Specialty type: Transplantation

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

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P-Reviewer: Liatsos GD S-Editor: Gong ZM L-Editor: A E-Editor: Wu YXJ

References
1.  Beam E, Razonable RR. Cytomegalovirus in solid organ transplantation: epidemiology, prevention, and treatment. Curr Infect Dis Rep. 2012;14:633-641.  [PubMed]  [DOI]
2.  Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50:1439-1447.  [PubMed]  [DOI]
3.  Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20:202-213.  [PubMed]  [DOI]
4.  Razonable RR, Paya CV. Herpesvirus infections in transplant recipients: current challenges in the clinical management of cytomegalovirus and Epstein-Barr virus infections. Herpes. 2003;10:60-65.  [PubMed]  [DOI]
5.  Meesing A, Razonable RR. New Developments in the Management of Cytomegalovirus Infection After Transplantation. Drugs. 2018;78:1085-1103.  [PubMed]  [DOI]
6.  Zuhair M, Smit GSA, Wallis G, Jabbar F, Smith C, Devleesschauwer B, Griffiths P. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol. 2019;29:e2034.  [PubMed]  [DOI]
7.  Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13512.  [PubMed]  [DOI]
8.  Paya CV, Marin E, Keating M, Dickson R, Porayko M, Wiesner R. Solid organ transplantation: results and implications of acyclovir use in liver transplants. J Med Virol. 1993;Suppl 1:123-127.  [PubMed]  [DOI]
9.  Humar A, Snydman D; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9 Suppl 4:S78-S86.  [PubMed]  [DOI]
10.  Singh N, Wannstedt C, Keyes L, Wagener MM, Cacciarelli TV. Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection? Liver Transpl. 2005;11:700-704.  [PubMed]  [DOI]
11.  Gane E, Saliba F, Valdecasas GJ, O'Grady J, Pescovitz MD, Lyman S, Robinson CA. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group [corrected]. Lancet. 1997;350:1729-1733.  [PubMed]  [DOI]
12.  Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017;64:87-91.  [PubMed]  [DOI]
13.  Collins-McMillen D, Buehler J, Peppenelli M, Goodrum F. Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation. Viruses. 2018;10.  [PubMed]  [DOI]
14.  Winston DJ, Emmanouilides C, Busuttil RW. Infections in liver transplant recipients. Clin Infect Dis. 1995;21:1077-89; quiz 1090-1.  [PubMed]  [DOI]
15.  Razonable R. Direct and indirect effects of cytomegalovirus: can we prevent them? Enferm Infecc Microbiol Clin. 2010;28:1-5.  [PubMed]  [DOI]
16.  Razonable RR, Paya CV, Smith TF. Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients. J Clin Microbiol. 2002;40:746-752.  [PubMed]  [DOI]
17.  Manuel O, Husain S, Kumar D, Zayas C, Mawhorter S, Levi ME, Kalpoe J, Lisboa L, Ely L, Kaul DR, Schwartz BS, Morris MI, Ison MG, Yen-Lieberman B, Sebastian A, Assi M, Humar A. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clin Infect Dis. 2013;56:817-824.  [PubMed]  [DOI]
18.  Lautenschlager I, Halme L, Höckerstedt K, Krogerus L, Taskinen E. Cytomegalovirus infection of the liver transplant: virological, histological, immunological, and clinical observations. Transpl Infect Dis. 2006;8:21-30.  [PubMed]  [DOI]
19.  Gardiner BJ, Nierenberg NE, Chow JK, Ruthazer R, Kent DM, Snydman DR. Absolute Lymphocyte Count: A Predictor of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients. Clin Infect Dis. 2018;67:1395-1402.  [PubMed]  [DOI]
20.  Meesing A, Abraham RS, Razonable RR. Clinical Correlation of Cytomegalovirus Infection With CMV-specific CD8+ T-cell Immune Competence Score and Lymphocyte Subsets in Solid Organ Transplant Recipients. Transplantation. 2019;103:832-838.  [PubMed]  [DOI]
21.  Brennan DC, Legendre C, Patel D, Mange K, Wiland A, McCague K, Shihab FS. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant. 2011;11:2453-2462.  [PubMed]  [DOI]
22.  Gala-Lopez BL, Senior PA, Koh A, Kashkoush SM, Kawahara T, Kin T, Humar A, Shapiro AM. Late cytomegalovirus transmission and impact of T-depletion in clinical islet transplantation. Am J Transplant. 2011;11:2708-2714.  [PubMed]  [DOI]
23.  Portela D, Patel R, Larson-Keller JJ, Ilstrup DM, Wiesner RH, Steers JL, Krom RA, Paya CV. OKT3 treatment for allograft rejection is a risk factor for cytomegalovirus disease in liver transplantation. J Infect Dis. 1995;171:1014-1018.  [PubMed]  [DOI]
24.  Pascual J, Royuela A, Fernández AM, Herrero I, Delgado JF, Solé A, Guirado L, Serrano T, de la Torre-Cisneros J, Moreno A, Cordero E, Gallego R, Lumbreras C, Aguado JM; Spanish Society of Transplantation Virological and Immune Response Investigation Study Group. Role of mTOR inhibitors for the control of viral infection in solid organ transplant recipients. Transpl Infect Dis. 2016;18:819-831.  [PubMed]  [DOI]
25.  Razonable RR, Rivero A, Rodriguez A, Wilson J, Daniels J, Jenkins G, Larson T, Hellinger WC, Spivey JR, Paya CV. Allograft rejection predicts the occurrence of late-onset cytomegalovirus (CMV) disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral ganciclovir. J Infect Dis. 2001;184:1461-1464.  [PubMed]  [DOI]
26.  Ambrose T, Sharkey LM, Louis-Auguste J, Rutter CS, Duncan S, English S, Gkrania-Klotsas E, Carmichael A, Woodward JM, Russell N, Massey D, Butler A, Middleton S. Cytomegalovirus Infection and Rates of Antiviral Resistance Following Intestinal and Multivisceral Transplantation. Transplant Proc. 2016;48:492-496.  [PubMed]  [DOI]
27.  Nagai S, Mangus RS, Anderson E, Ekser B, Kubal CA, Fridell JA, Tector AJ. Cytomegalovirus Infection After Intestinal/Multivisceral Transplantation: A Single-Center Experience With 210 Cases. Transplantation. 2016;100:451-460.  [PubMed]  [DOI]
28.  Beam E, Lesnick T, Kremers W, Kennedy CC, Razonable RR. Cytomegalovirus disease is associated with higher all-cause mortality after lung transplantation despite extended antiviral prophylaxis. Clin Transplant. 2016;30:270-278.  [PubMed]  [DOI]
29.  Humar A, Gregson D, Caliendo AM, McGeer A, Malkan G, Krajden M, Corey P, Greig P, Walmsley S, Levy G, Mazzulli T. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation. 1999;68:1305-1311.  [PubMed]  [DOI]
30.  Singh N, Wagener MM. Strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2006;144:456-7; author reply 457.  [PubMed]  [DOI]
31.  Razonable RR. Cytomegalovirus infection after liver transplantation: current concepts and challenges. World J Gastroenterol. 2008;14:4849-4860.  [PubMed]  [DOI]
32.  Manuel O, Pang XL, Humar A, Kumar D, Doucette K, Preiksaitis JK. An assessment of donor-to-recipient transmission patterns of human cytomegalovirus by analysis of viral genomic variants. J Infect Dis. 2009;199:1621-1628.  [PubMed]  [DOI]
33.  Fernández-Ruiz M, Giménez E, Vinuesa V, Ruiz-Merlo T, Parra P, Amat P, Montejo M, Paez-Vega A, Cantisán S, Torre-Cisneros J, Fortún J, Andrés A, San Juan R, López-Medrano F, Navarro D, Aguado JM; Group for Study of Infection in Transplantation of the Spanish Society of Infectious Diseases and Clinical Microbiology (GESITRA-SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI). Regular monitoring of cytomegalovirus-specific cell-mediated immunity in intermediate-risk kidney transplant recipients: predictive value of the immediate post-transplant assessment. Clin Microbiol Infect. 2019;25:381.e1-381.e10.  [PubMed]  [DOI]
34.  Razonable RR, Emery VC; 11th Annual Meeting of the IHMF (International Herpes Management Forum). Management of CMV infection and disease in transplant patients. 27-29 February 2004. Herpes. 2004;11:77-86.  [PubMed]  [DOI]
35.  Cohen JI, Corey GR. Cytomegalovirus infection in the normal host. Medicine (Baltimore). 1985;64:100-114.  [PubMed]  [DOI]
36.  Paya CV, Hermans PE, Wiesner RH, Ludwig J, Smith TF, Rakela J, Krom RA. Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations. J Infect Dis. 1989;160:752-758.  [PubMed]  [DOI]
37.  Shusterman NH, Frauenhoffer C, Kinsey MD. Fatal massive hepatic necrosis in cytomegalovirus mononucleosis. Ann Intern Med. 1978;88:810-812.  [PubMed]  [DOI]
38.  Tjwa M, De Hertogh G, Neuville B, Roskams T, Nevens F, Van Steenbergen W. Hepatic fibrin-ring granulomas in granulomatous hepatitis: report of four cases and review of the literature. Acta Clin Belg. 2001;56:341-348.  [PubMed]  [DOI]
39.  Clarke J, Craig RM, Saffro R, Murphy P, Yokoo H. Cytomegalovirus granulomatous hepatitis. Am J Med. 1979;66:264-269.  [PubMed]  [DOI]
40.  You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep. 2012;14:334-342.  [PubMed]  [DOI]
41.  Patra S, Samal SC, Chacko A, Mathan VI, Mathan MM. Cytomegalovirus infection of the human gastrointestinal tract. J Gastroenterol Hepatol. 1999;14:973-976.  [PubMed]  [DOI]
42.  Lee CY, Chen YH, Lu PL. Reactivated cytomegalovirus proctitis in an immunocompetent patient presenting as nosocomial diarrhea: a case report and literature review. BMC Infect Dis. 2017;17:113.  [PubMed]  [DOI]
43.  Jacob S, Zayyani NR. Cytomegalovirus colitis masquerading as rectal malignancy in an immunocompetent patient. Indian J Pathol Microbiol. 2015;58:80-82.  [PubMed]  [DOI]
44.  Razonable RR, Humar A; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:93-106.  [PubMed]  [DOI]
45.  Aguilera V, Di Maira T, Conde I, Fornés-Ferrer V, Vinaixa C, Pallarés C, Carvalho-Gomes A, Cubells A, García M, Rubín Á, Benlloch S, Gonzalez-Dieguez L, Molina JM, Puchades L, López-Labrador FX, Prieto M, Berenguer M. Cytomegalovirus reactivation in liver transplant recipients due to hepatitis C cirrhosis is associated with higher cardiovascular risk - an observational, retrospective study. Transpl Int. 2018;31:649-657.  [PubMed]  [DOI]
46.  Mendez JC, Dockrell DH, Espy MJ, Smith TF, Wilson JA, Harmsen WS, Ilstrup D, Paya CV. Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis. 2001;183:179-184.  [PubMed]  [DOI]
47.  Halling VW, Maine GT, Groettum CM, Wilson JA, Spesard J, Brojanac S, Combs B, Wachta D, Holas C, Wilson T, Wang D, Tomazic-Allen S, Lazzarotto T, Landini MP, Jevremovic-Simovic S, Wiesner RH, Paya CV, Smith TF. Clinical evaluation of a new recombinant antigen-based cytomegalovirus immunoglobulin M immunoassay in liver transplant recipients. Transplantation. 2001;71:395-397.  [PubMed]  [DOI]
48.  Dioverti MV, Razonable RR. Cytomegalovirus. Microbiol Spectr. 2016;4.  [PubMed]  [DOI]
49.  Patel R, Snydman DR, Rubin RH, Ho M, Pescovitz M, Martin M, Paya CV. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation. 1996;61:1279-1289.  [PubMed]  [DOI]
50.  Razonable RR, Brown RA, Wilson J, Groettum C, Kremers W, Espy M, Smith TF, Paya CV. The clinical use of various blood compartments for cytomegalovirus (CMV) DNA quantitation in transplant recipients with CMV disease. Transplantation. 2002;73:968-973.  [PubMed]  [DOI]
51.  Lepinski SM, Hamilton JW. Isolated cytomegalovirus ileitis detected by colonoscopy. Gastroenterology. 1990;98:1704-1706.  [PubMed]  [DOI]
52.  Navaneethan U, Venkatesh PG, Wang J. Cytomegalovirus ileitis in a patient after liver transplantation-differentiating from de novo IBD. J Crohns Colitis. 2011;5:354-359.  [PubMed]  [DOI]
53.  Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, Norman D, Mendez R, Keating MR, Coggon GL, Crisp A, Lee IC. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med. 1999;340:1462-1470.  [PubMed]  [DOI]
54.  Bodro M, Sabé N, Lladó L, Baliellas C, Niubó J, Castellote J, Fabregat J, Rafecas A, Carratalà J. Prophylaxis versus preemptive therapy for cytomegalovirus disease in high-risk liver transplant recipients. Liver Transpl. 2012;18:1093-1099.  [PubMed]  [DOI]
55.  Simon P, Sasse M, Laudi S, Petroff D, Bartels M, Kaisers UX, Bercker S. Two strategies for prevention of cytomegalovirus infections after liver transplantation. World J Gastroenterol. 2016;22:3412-3417.  [PubMed]  [DOI]
56.  Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD; Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004;4:611-620.  [PubMed]  [DOI]
57.  Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017;377:2433-2444.  [PubMed]  [DOI]
58.  Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, Sgarabotto D, Tuncer M, Noronha IL, Hartmann A; VICTOR Study Group. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7:2106-2113.  [PubMed]  [DOI]
59.  Levitsky J, Singh N, Wagener MM, Stosor V, Abecassis M, Ison MG. A survey of CMV prevention strategies after liver transplantation. Am J Transplant. 2008;8:158-161.  [PubMed]  [DOI]
60.  Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, Abramowicz D, Jardine AG, Voulgari AT, Ives J, Hauser IA, Peeters P. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10:1228-1237.  [PubMed]  [DOI]
61.  Hirsch HH, Lautenschlager I, Pinsky BA, Cardeñoso L, Aslam S, Cobb B, Vilchez RA, Valsamakis A. An international multicenter performance analysis of cytomegalovirus load tests. Clin Infect Dis. 2013;56:367-373.  [PubMed]  [DOI]
62.  Sia IG, Wilson JA, Groettum CM, Espy MJ, Smith TF, Paya CV. Cytomegalovirus (CMV) DNA load predicts relapsing CMV infection after solid organ transplantation. J Infect Dis. 2000;181:717-720.  [PubMed]  [DOI]
63.  Avery RK, Arav-Boger R, Marr KA, Kraus E, Shoham S, Lees L, Trollinger B, Shah P, Ambinder R, Neofytos D, Ostrander D, Forman M, Valsamakis A. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation. 2016;100:e74-e80.  [PubMed]  [DOI]
64.  Asberg A, Humar A, Jardine AG, Rollag H, Pescovitz MD, Mouas H, Bignamini A, Töz H, Dittmer I, Montejo M, Hartmann A; VICTOR Study Group. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am J Transplant. 2009;9:1205-1213.  [PubMed]  [DOI]
65.  Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Clinical predictors of relapse after treatment of primary gastrointestinal cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2010;10:157-161.  [PubMed]  [DOI]
66.  Gardiner BJ, Chow JK, Price LL, Nierenberg NE, Kent DM, Snydman DR. Role of Secondary Prophylaxis With Valganciclovir in the Prevention of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients. Clin Infect Dis. 2017;65:2000-2007.  [PubMed]  [DOI]
67.  Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci USA. 2000;97:8039-8044.  [PubMed]  [DOI]
68.  Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet. 2000;356:645-649.  [PubMed]  [DOI]
69.  Myhre HA, Haug Dorenberg D, Kristiansen KI, Rollag H, Leivestad T, Asberg A, Hartmann A. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation. 2011;92:217-223.  [PubMed]  [DOI]
70.  Czarnecka P, Czarnecka K, Tronina O, Durlik M. Cytomegalovirus Disease After Liver Transplant-A Description of a Treatment-Resistant Case: A Case Report and Literature Review. Transplant Proc. 2018;50:4015-4022.  [PubMed]  [DOI]