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Akingbola A, Adegbesan A, Adewole O, Adegoke K, Benson AE, Jombo PA, Uchechukwu Eboson S, Oluwasola V, Aiyenuro A. The mRNA-1647 vaccine: A promising step toward the prevention of cytomegalovirus infection (CMV). Hum Vaccin Immunother 2025; 21:2450045. [PMID: 39825496 DOI: 10.1080/21645515.2025.2450045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/14/2024] [Accepted: 01/02/2025] [Indexed: 01/30/2025] Open
Abstract
Cytomegalovirus (CMV) is a leading cause of congenital infections and significant health complications in immunocompromised individuals. With no licensed CMV vaccine available, the development of the mRNA-1647 offers promising advancements in CMV prevention. We have reviewed results from Phase 1 and 2 clinical trials of the mRNA-1647 vaccine, demonstrating robust immune responses in both seronegative and seropositive participants. Vaccines exhibited significantly elevated neutralizing antibody titers against CMV, particularly in fibroblast and epithelial cells, with sustained responses lasting up to 18 months post-vaccination. The mRNA-1647 vaccine triggered strong T-cell and memory B-cell responses, suggesting its potential for long-term protection against CMV infection. The ongoing Phase 3 CMVictory trial evaluates the safety and immunogenicity of mRNA-1647 in women of childbearing age, with preliminary data showing promise in preventing congenital CMV transmission. This vaccine could significantly reduce CMV-related morbidity and mortality, particularly in newborns and immunocompromised individuals, addressing a critical unmet medical need.
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Affiliation(s)
| | - Abiodun Adegbesan
- African Cancer Institute, Department of Global Health, Stellenbosch University, Cape Town, South Africa
| | | | - Kolade Adegoke
- Faculty of Clinical Sciences, Obafemi Awolowo University Ile-Ife, Osun State,Nigeria
| | | | - Paul Ayomide Jombo
- Internal Medicine, Basildon and Thurrock University Hospitals NHS Foundation Trust: Basildon SS165NL, England, Essex, England, UK
| | | | - Victor Oluwasola
- Babcock University Teaching Hospital, Ilishan-Remo, Ogun State, Nigeria
| | - Ademola Aiyenuro
- Division of Virology, Department of Pathology, University of Cambridge, England, UK
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2
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Fernández S, Castro P, Azoulay E. What intensivists need to know about cytomegalovirus infection in immunocompromised ICU patients. Intensive Care Med 2025; 51:39-61. [PMID: 39774866 DOI: 10.1007/s00134-024-07737-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/19/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE Advances in therapeutic care are leading to an increase in the number of patients living with overt immunosuppression. These patients are at risk of cytomegalovirus (CMV) infection and disease that can lead to or develop during ICU admission. This manuscript aims to describe the clinical presentation, risk factors, and management of CMV infection and disease in this patient population. METHODS We conducted a literature search in PubMed up to April 2024, focusing on CMV infection and disease in patients with overt immunosuppression (hematopoietic stem cell and solid organ transplantation, solid or hematologic malignancies, HIV infection, immunosuppressive drugs, including corticosteroids, and primary immunodeficiencies) admitted to the intensive care unit (ICU). As there is limited ICU-specific data on CMV in immunosuppressed patients, many of the findings were extrapolated from the general literature. RESULTS CMV infection and disease in immunocompromised critically ill patients is associated with increased mortality and presents significant management challenges. Clinical manifestations are diverse, shaped by the underlying immune deficiency and primary disease. Pneumonia and encephalitis are among the most severe CMV end-organ diseases. CMV infection may also increase the risk of secondary infections and induce life-threatening conditions, such as thrombotic microangiopathy. Importantly, CMV reactivation is not synonymous with CMV disease, and qPCR testing of body fluids cannot reliably differentiate between viral shedding and tissue-invasive infection, which requires histopathological confirmation. Ganciclovir is commonly the first-line anti-viral, though maribavir shows potential for patients unresponsive to other antivirals. Identifying patients who require prophylactic or preemptive antiviral therapy is essential. CONCLUSIONS CMV infection and disease in critically ill immunocompromised patients pose a unique challenge for intensivists. The broad spectrum of clinical presentations and the difficulty in distinguishing CMV-related symptoms from other causes require a high level of clinical suspicion. Accurate interpretation of nucleic acid load levels and careful evaluation of CMV's pathogenic role when it is found are critical. Further studies focusing specifically on CMV infection and disease in critically ill immunocompromised patients are needed to optimize management strategies.
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Affiliation(s)
- Sara Fernández
- Medical Intensive Care Unit, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
- Medical Intensive Care Unit, AP-HP, Saint-Louis University Hospital, Paris, France.
| | - Pedro Castro
- Medical Intensive Care Unit, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Elie Azoulay
- Medical Intensive Care Unit, AP-HP, Saint-Louis University Hospital, Paris, France
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3
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Odenwald MA, Roth HF, Reticker A, Segovia M, Pillai A. Evolving challenges with long-term care of liver transplant recipients. Clin Transplant 2023; 37:e15085. [PMID: 37545440 DOI: 10.1111/ctr.15085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/08/2023]
Abstract
The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.
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Affiliation(s)
- Matthew A Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Hannah F Roth
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Anesia Reticker
- Department of Pharmacy, University of Chicago Medicine, Chicago, USA
| | - Maria Segovia
- Department of Medicine, Section of Gastroenterology, Duke University School of Medicine, Durham, USA
| | - Anjana Pillai
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
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4
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Gupta M, Manek G, Dombrowski K, Maiwall R. Newer developments in viral hepatitis: Looking beyond hepatotropic viruses. World J Meta-Anal 2021; 9:522-542. [DOI: 10.13105/wjma.v9.i6.522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/09/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis in the entirety of its clinical spectrum is vast and most discussion are often restricted to hepatotropic viral infections, including hepatitis virus (A to E). With the advent of more advanced diagnostic techniques, it has now become possible to diagnose patients with non-hepatotropic viral infection in patients with hepatitis. Majority of these viruses belong to the Herpes family, with characteristic feature of latency. With the increase in the rate of liver transplantation globally, especially for the indication of acute hepatitis, it becomes even more relevant to identify non hepatotropic viral infection as the primary hepatic insult. Immunosuppression post-transplant is an established cause of reactivation of a number of viral infections that could then indirectly cause hepatic injury. Antiviral agents may be utilized for treatment of most of these infections, although data supporting their role is derived primarily from case reports. There are no current guidelines to manage patients suspected to have viral hepatitis secondary to non-hepatotropic viral infection, a gap that needs to be addressed. In this review article, the authors analyze the common non hepatotropic viral infections contributing to viral hepatitis, with emphasis on recent advances on diagnosis, management and role of liver transplantation.
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Affiliation(s)
- Manasvi Gupta
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06030, United States
| | - Gaurav Manek
- Department of Pulmonology and Critical Care, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Kaitlyn Dombrowski
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06030, United States
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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5
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Da Cunha T, Wu GY. Cytomegalovirus Hepatitis in Immunocompetent and Immunocompromised Hosts. J Clin Transl Hepatol 2021; 9:106-115. [PMID: 33604261 PMCID: PMC7868697 DOI: 10.14218/jcth.2020.00088] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/22/2020] [Accepted: 12/08/2020] [Indexed: 12/25/2022] Open
Abstract
Human cytomegalovirus (HCMV) infection is common and affects between 40-100% of the worldwide population. However, the majority of cases are asymptomatic and when severe disease occurs, it is usually restricted to immunocompromised patients. Liver involvement by HCMV differs significantly, accordingly to the immune status of the host. In immunocompromised patients, particularly liver transplant patients, it often causes clinically significant hepatitis. On the other hand, in immunocompetent patients, HCMV hepatitis requiring hospitalization is extremely rare. This review aims to appraise studies regarding the pathophysiology of HCMV hepatitis, including mechanisms of latency and reactivation and its contribution to disease development, clinical presentation, diagnostic modalities and treatment, with a focus on comparing different aspects between immunocompromised and immunocompetent hosts.
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Affiliation(s)
- Teresa Da Cunha
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Teresa Da Cunha, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA. Tel: +1-860-706-2133, Fax: +1-860-679-3159, E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Current address: Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
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6
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Lizaola-Mayo BC, Rodriguez EA. Cytomegalovirus infection after liver transplantation. World J Transplant 2020; 10:183-190. [PMID: 32844094 PMCID: PMC7416364 DOI: 10.5500/wjt.v10.i7.183] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/28/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
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.
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Affiliation(s)
- 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
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7
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Jothimani D, Venugopal R, Vij M, Rela M. Post liver transplant recurrent and de novo viral infections. Best Pract Res Clin Gastroenterol 2020; 46-47:101689. [PMID: 33158469 PMCID: PMC7519014 DOI: 10.1016/j.bpg.2020.101689] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 01/31/2023]
Abstract
Survival following liver transplantation has changed dramatically owing to improvement in surgical techniques, peri-operative care and optimal immunosuppressive therapy. Post-Liver transplant (LT) de novo or recurrent viral infection continues to cause major allograft dysfunction, leading to poor graft and patient survival in untreated patients. Availability of highly effective antiviral drugs has significantly improved post-LT survival. Patients transplanted for chronic hepatitis B infection should receive life-long nucleos(t)ide analogues, with or without HBIg for effective viral control. Patients with chronic hepatitis C should be commenced on directly acting antiviral (DAA) drugs prior to transplantation. DAA therapy for post-LT recurrent hepatitis C infection is associated with close to 100% sustained virological response (SVR), irrespective of genotype. De novo chronic Hepatitis E infection is an increasingly recognised cause of allograft dysfunction in LT recipients. Untreated chronic HEV infection of the graft may lead to liver fibrosis and allograft failure. CMV and EBV can reactivate leading to systemic illness following liver transplantation. With COVID-19 pandemic, post-transplant patients are at risk of SARS-Co-V2 infection. Majority of the LT recipients require hospitalization, and the mortality in this population is around 20%. Early recognition of allograft dysfunction and identification of viral aetiology is essential in the management of post-LT de novo or recurrent infections. Optimising immunosuppression is an important step in reducing the severity of allograft damage in the treatment of post-transplant viral infections. Viral clearance or control can be achieved by early initiation of high potency antiviral therapy.
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Affiliation(s)
- Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
| | - Radhika Venugopal
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India
| | - Mukul Vij
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India
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8
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Bunchorntavakul C, Reddy KR. Epstein-Barr Virus and Cytomegalovirus Infections of the Liver. Gastroenterol Clin North Am 2020; 49:331-346. [PMID: 32389366 DOI: 10.1016/j.gtc.2020.01.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections are common and are associated with a variety of liver manifestations. EBV and CMV infections, in immunocompetent hosts, commonly manifest as acute hepatitis, with severity varying from asymptomatic, self-limited icteric hepatitis to acute liver failure. Atypical manifestations, such as cholestasis, chronic hepatitis, precipitation of acute-on-chronic liver failure, and autoimmune hepatitis, are reported with EBV infection, whereas cholestasis, portal vein thrombosis, and Budd-Chiari syndrome are reported with CMV infection. In the setting of liver transplantation, CMV is the most common infectious complication and carries significant morbidity; EBV is the major cause of post-transplant lymphoproliferative disorders.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, 2 Phayathai Road, Ratchathewi, Bangkok 10400, Thailand
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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9
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Abstract
Liver transplantation has become an important treatment modality for patients with end-stage liver disease/cirrhosis, acute liver failure, and hepatocellular carcinoma. Although surgical techniques and immunosuppressive regimens for liver transplantation have improved significantly over the past 20 years, infectious complications continue to contribute to the morbidity and mortality in this patient population. The use of standardized screening protocols for both donors and recipients, coupled with targeted prophylaxis against specific pathogens, has helped to mitigate the risk of infection in liver transplant recipients. Patients with chronic liver disease and cirrhosis have immunological deficits that place them at increased risk for infection while awaiting liver transplantation. The patient undergoing liver transplantation is prone to develop healthcare-acquired infections due to multidrug-resistant organisms that could potentially affect patient outcomes after transplantation. The complex nature of liver transplant surgery that involves multiple vascular and hepatobiliary anastomoses further increases the risk of infection after liver transplantation. During the early post-transplantation period, healthcare-acquired bacterial and fungal infections are the most common types of infection encountered in liver transplant recipients. The period of maximal immunosuppression that occurs at 1–6 months after transplantation can be complicated by opportunistic infections due to both primary infection and reactivation of latent infection. Severe community-acquired infections can complicate the course of liver transplantation beyond 12 months after transplant surgery. This chapter provides an overview of liver transplantation including indications, donor-recipient selection criteria, surgical procedures, and immunosuppressive therapies. A focus on infections in patients with chronic liver disease/cirrhosis and an overview of the specific infectious complications in liver transplant recipients are presented.
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10
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Weizman OE, Adams NM, Schuster IS, Krishna C, Pritykin Y, Lau C, Degli-Esposti MA, Leslie CS, Sun JC, O'Sullivan TE. ILC1 Confer Early Host Protection at Initial Sites of Viral Infection. Cell 2017; 171:795-808.e12. [PMID: 29056343 DOI: 10.1016/j.cell.2017.09.052] [Citation(s) in RCA: 347] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/11/2017] [Accepted: 08/16/2017] [Indexed: 10/18/2022]
Abstract
Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Whether tissue-resident lymphocytes confer early antiviral immunity at local sites of primary infection prior to the initiation of circulating responses is not well understood. Furthermore, the kinetics of initial antiviral responses at sites of infection remain unclear. Here, we show that tissue-resident type 1 innate lymphoid cells (ILC1) serve an essential early role in host immunity through rapid production of interferon (IFN)-γ following viral infection. Ablation of Zfp683-dependent liver ILC1 lead to increased viral load in the presence of intact adaptive and innate immune cells critical for mouse cytomegalovirus (MCMV) clearance. Swift production of interleukin (IL)-12 by tissue-resident XCR1+ conventional dendritic cells (cDC1) promoted ILC1 production of IFN-γ in a STAT4-dependent manner to limit early viral burden. Thus, ILC1 contribute an essential role in viral immunosurveillance at sites of initial infection in response to local cDC1-derived proinflammatory cytokines.
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Affiliation(s)
- Orr-El Weizman
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Nicholas M Adams
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Iona S Schuster
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia
| | - Chirag Krishna
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Yuri Pritykin
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Colleen Lau
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mariapia A Degli-Esposti
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia
| | - Christina S Leslie
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Joseph C Sun
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA.
| | - Timothy E O'Sullivan
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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11
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12
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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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Luscalov S, Loga L, Dican L, Junie LM. Cytomegalovirus infection in immunosuppressed patients after kidney transplantation. Med Pharm Rep 2016; 89:343-6. [PMID: 27547053 PMCID: PMC4990428 DOI: 10.15386/cjmed-587] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 10/25/2015] [Indexed: 12/15/2022] Open
Abstract
The first kidney transplantation was performed in 1951 and ever since then living donor transplantation became a more and more important solution for patients with end-stage renal disease (ESRD). Renal transplantation is a life-saving procedure. Morbidity and mortality on waiting-lists are strongly correlated with the time of dialysis and end-stage renal disease is one of the most important causes of death; this is the reason why transplantation has to be performed as soon as possible in order to reduce the time of dialysis. Once the transplantation is performed, a number of complications may occur in post-transplant evolution, the most important of which is rejection. The rejection may appear through several mechanisms, but one of the most frequent causes of rejection is cytomegalovirus (CMV) infection. It is very important to have a precocious and fast diagnosis of CMV infection in order to maintain the functionality and survival of the graft. PP65 CMV antigenemia has proven its effectiveness in detecting and monitoring the CMV infection in transplanted patients. In the laboratory of the Clinical Institute of Urology and Renal Transplantation (ICUTR) of Cluj Napoca the CMV infection is evidenced by two methods: PP65antigenemia and IgM antibody identification by chemiluminiscence.
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Affiliation(s)
- Simona Luscalov
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | - Lucia Dican
- Departament of Biochemistry, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lia Monica Junie
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Schupp AK, Trilling M, Rattay S, Le-Trilling VTK, Haselow K, Stindt J, Zimmermann A, Häussinger D, Hengel H, Graf D. Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes. J Virol 2016; 90:6686-6698. [PMID: 27170759 PMCID: PMC4944301 DOI: 10.1128/jvi.00299-16] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/06/2016] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-α) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-γ. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells. IMPORTANCE Cytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds.
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Affiliation(s)
- Anna-Kathrin Schupp
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany
| | - Mirko Trilling
- Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stephanie Rattay
- Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Vu Thuy Khanh Le-Trilling
- Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katrin Haselow
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany
| | - Albert Zimmermann
- Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany
| | - Hartmut Hengel
- Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany
- Department for Medical Microbiology and Hygiene, Institute of Virology, Albert-Ludwigs-University, Freiburg, Germany
| | - Dirk Graf
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany
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15
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DelBuono EA, Appelman HD, Frank TS. Role of Polymerase Chain Reaction in the Diagnosis of Cytomegalovirus Infection in Liver Transplant Patients. Int J Surg Pathol 2016. [DOI: 10.1177/106689699500200308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Eighty-eight formalin-fixed, paraffin-embedded needle biopsies from 58 liver trans plant recipients were analyzed for the presence of cytomegalovirus (CMV) by light microscopy and the polymerase chain reaction (PCR). Twenty-seven biopsies were positive for CMV by both light microscopy and PCR, 41 were negative by both methods, 17 were positive by PCR only, and 3 were positive by light microscopy only. In the absence of cytomegalic cells, immunohistochemical staining was unable to detect CMV that could have been identified by PCR. Serum total bilirubin was higher in patients whose biopsies contained PCR (but not histologic) evidence of CMV infection. No evidence of association of the presence of CMV was found by either PCR or light microscopy with serum levels of aminotransferase or alkaline phosphatase, nor with histologic evidence of rejection or hepatitis. PCR was negative for CMV in 22 liver biopsies from immunocompetent individuals without evidence of hepatic dysfunction. Although PCR can detect the presence of CMV in the absence of cytomegalic cells, the clinical significance of PCR-proven, histologically undetectable CMV in the liver is undetermined. Int J Surg Pathol 2(3):221-226, 1995
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Gotthardt DN, Senft J, Sauer P, Weiss KH, Flechtenmacher C, Eckerle I, Schaefer Y, Schirmacher P, Stremmel W, Schemmer P, Schnitzler P. Occult cytomegalovirus cholangitis as a potential cause of cholestatic complications after orthotopic liver transplantation? A study of cytomegalovirus DNA in bile. Liver Transpl 2013; 19:1142-1150. [PMID: 23894112 DOI: 10.1002/lt.23713] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 06/30/2013] [Indexed: 12/29/2022]
Abstract
Cholestatic complications, important causes of morbidity and mortality after orthotopic liver transplantation (OLT), often have an unclear etiology. Human cytomegalovirus (CMV) infections occur in immunosuppressed patients and can be detected in blood samples. However, CMV analyses of body fluids and biopsies are more sensitive. Here we evaluated whether a CMV analysis of bile could reveal occult CMV cholangitis. We evaluated OLT patients undergoing endoscopic retrograde cholangiography (ERC) for suspected biliary complications after OLT at a tertiary care center. Biliary CMV DNA levels were measured with real-time polymerase chain reaction. A nonanastomotic biliary lesion (NABL) group consisted of patients with nonanastomotic strictures (NASs) at the time of ERC (n = 59) and patients with normal ERC findings but microscopic biliary lesions in biopsy samples (n = 12). The anastomotic stricture (AS) group comprised patients with ASs only (n = 53). In all, 124 OLT patients underwent 240 ERC procedures. Biliary CMV DNA was detected in 14 of the 124 patients and was more frequently found in the NABL group (12/71 for the NABL group versus 2/53 for the AS group, P = 0.02). Concurrent sampling of CMV DNA in blood yielded negative results. Biliary CMV was more frequently detected in patients with a positive recipient status (13/73 or 17.8% versus 1/44 or 2.3%, P < 0.05). There was no significant difference in the incidence of biliary CMV between patients with a high-risk CMV status and patients with a low-risk CMV status. The median interval between OLT and biliary CMV detection was 8.4 months (range = 0.4-212.8 months). In conclusion, biliary CMV was detected in a substantial number of patients after OLT and was significantly associated with NASs or microscopic biliary lesions. A potential occult CMV infection could, therefore, be considered as a contributory etiological factor in the development of biliary complications.
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Affiliation(s)
- Daniel Nils Gotthardt
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany
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17
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Kawahara T, Lisboa LF, Cader S, Douglas DN, Nourbakhsh M, Pu CH, Lewis JT, Churchill TA, Humar A, Kneteman NM. Human cytomegalovirus infection in humanized liver chimeric mice. Hepatol Res 2013; 43:679-84. [PMID: 23442000 DOI: 10.1111/j.1872-034x.2012.01116.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 10/02/2012] [Accepted: 10/04/2012] [Indexed: 02/08/2023]
Abstract
AIM Cytomegalovirus is a common viral pathogen that influences the outcome of organ transplantation. To date, there is no established method to evaluate the effects of human CMV (HCMV) treatments in vivo except for human clinical trials. In the current study, we describe the development of a mouse model that supports the in vivo propagation of HCMV. METHODS One million viable human hepatocytes, purified from human livers, were injected into the spleens of severe combined immunodeficient/albumin linked-urokinase type plasminogen activator transgenic mice. A clinical strain of HCMV was inoculated in mice with confirmed human hepatocyte engraftment or in non-chimeric controls. Infection was monitored through HCMV titers in the plasma. Mice were administrated ganciclovir (50 mg/kg per day, i.p.) beginning at 2 days post-HCMV inoculation, or human liver natural killer (NK) cells (20 × 10(6) cells/mouse, i.v.) 1 day prior to HCMV inoculation. RESULTS Chimeric mice that received HCMV showed high plasma titers of HCMV DNA on days 1 and 6 that became undetectable by day 11 post-inoculation. In contrast, non-transplanted mice had only residual plasma inoculum detection at day 1 and no detectable viremia thereafter. The levels of HCMV DNA were reduced by ganciclovir treatment or by human liver NK cell adoptive transfer, while HCMV-infected chimeric mice that were not treated sustained viremia during the follow up. CONCLUSION Human liver chimeric mice provide an in vivo model for the study of acute HCMV infection of hepatocytes.
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Affiliation(s)
- Toshiyasu Kawahara
- Division of Transplantation Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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18
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Naini BV, Lassman CR. Liver Transplant Pathology: Review of Challenging Diagnostic Situations. Surg Pathol Clin 2013; 6:277-93. [PMID: 26838975 DOI: 10.1016/j.path.2013.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Histopathologic assessment of allograft liver biopsies has an important role in managing patients who have undergone liver transplantation. In this review, several topics are discussed that create diagnostic problems in transplant pathology, with emphasis on pathologic features and differential diagnosis. The topics discussed are acute cellular rejection, late acute rejection (centrizonal/parenchymal rejection), chronic rejection, plasma cell hepatitis, idiopathic posttransplant chronic hepatitis, fibrosing cholestatic hepatitis, selected viral infections (cytomegalovirus, Epstein-Barr virus, and hepatitis E), and acute antibody-mediated rejection.
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Affiliation(s)
- Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 1P-172 CHS, Los Angeles, CA 90095-1732, USA.
| | - Charles R Lassman
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 13-145 CHS, Los Angeles, CA 90095-1732, USA
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19
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Cytomegalovirus Infection in Liver Transplant Recipients. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2012. [DOI: 10.1097/ipc.0b013e31823c4817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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20
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Indolfi G, Heaton N, Smith M, Mieli-Vergani G, Zuckerman M. Effect of early EBV and/or CMV viremia on graft function and acute cellular rejection in pediatric liver transplantation. Clin Transplant 2011; 26:E55-61. [DOI: 10.1111/j.1399-0012.2011.01535.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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21
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Bosch W, Heckman MG, Diehl NN, Shalev JA, Pungpapong S, Hellinger WC. Association of cytomegalovirus infection and disease with death and graft loss after liver transplant in high-risk recipients. Am J Transplant 2011; 11:2181-9. [PMID: 21827609 DOI: 10.1111/j.1600-6143.2011.03618.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In the era of effective antiviral chemoprophylaxis, cytomegalovirus (CMV) disease has been inconsistently associated with increased mortality in liver transplant (LT) recipients. A retrospective study evaluating the association of CMV infection and disease occurring within 1 year of transplant with the endpoints of death or the combined endpoint of graft loss or death was undertaken in a cohort of 227 CMV donor seropositive, recipient seronegative first LT recipients. Associations were evaluated using Cox proportional hazards regression models. CMV infection and disease occurred in 91 (40%) and 43 (19%) patients, respectively. Forty-eight (21%) died while 58 (26%) sustained graft loss or death. In multivariable analysis, CMV infection was associated with an increased risk of death (RR: 2.24, p = 0.008) and graft loss or death (RR: 2.85, p < 0.001). CMV disease was also associated with an increased risk of death (RR: 2.73, p = 0.003) and graft loss or death (RR: 3.04, p = 0.001). CMV infection and disease occurring within the first year after LT in high-risk recipients is associated with increased risk of death and of graft loss or death. Investigation of strategies to further reduce the risk of CMV infection and disease in high-risk LT recipients is warranted.
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Affiliation(s)
- W Bosch
- Division of Infectious Diseases Division of Biostatistics Division of Transplant Division of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL, USA.
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22
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Navaneethan U, Venkatesh PGK, Wang J. Cytomegalovirus ileitis in a patient after liver transplantation-differentiating from de novo IBD. J Crohns Colitis 2011; 5:354-9. [PMID: 21683307 DOI: 10.1016/j.crohns.2011.01.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2011] [Revised: 01/31/2011] [Accepted: 01/31/2011] [Indexed: 02/08/2023]
Abstract
Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract has been reported in immunocompromised patients and is seen following liver transplantation. Although CMV infection can affect any part of the GI tract, involvement of the terminal ileum is rarely encountered after liver transplantation. We report a case of a 32-year-old male who developed CMV infection of the terminal ileum while receiving immunosuppression for liver transplantation. Initial ganciclovir treatment did not improve the patient's symptoms and therapy was then switched to foscarnet which ultimately resulted in resolution of infection. However the patient continued to have symptoms because of intermittent small bowel obstruction because of ulcerations and fibrosis ultimately requiring surgical resection. CMV DNA polymerase chain reaction (PCR) was negative throughout the course of infection. Surgical resected specimen revealed no evidence of inflammatory bowel disease (IBD). Follow up colonoscopy up to a year after infection also did not reveal any evidence of IBD. Compartmentalization in the clinical presentation of CMV involving GI tract can be seen with a negative blood DNA PCR. Histological diagnosis thus forms an important part in the clinical follow-up of liver transplant patients undergoing intense immunosuppression and should be aggressively pursued in patients with GI symptoms. De novo IBD should be considered in the differential diagnosis in these patients who do not improve with anti-viral treatment.
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23
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Tabll A, Shoman S, Ghanem H, Nabil M, El Din NGB, El Awady MK. Assessment of human cytomegalovirus co-infection in Egyptian chronic HCV patients. Virol J 2011. [PMID: 21740595 DOI: 10.1186/1743-422x-8-343.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Human cytomegalovirus (HCMV) is the most common cause of severe morbidity and mortality in immune- compromised individuals. This study was conducted to determine the incidence of HCMV infection in HCV patients who either spontaneously cleared the virus or progressed to chronic HCV infection. The study included a total of eighty four cases (48 females and 36 males) that were referred to blood banks for blood donation with an age range of 18-64 years (mean age 37.62 ± 10.03 years). Hepatitis C virus RNA and HCMV DNA were detected in sera by RT-nested PCR and nested PCR respectively in all subjects. Immunoglobulin G levels for HCV and HCMV were determined. Besides, IgM antibodies for HCMV infection were also determined in subjects' sera. Fifty three out of 84 cases (63%) were positive for HCV-RNA while 31 (37%) cases had negative HCV RNA. Forty six (87%) and 13 (25%) cases out of 53 HCV RNA positive patients were positive for HCMV IgG and IgM antibodies respectively. While 20 of 53 cases (38%) had detectable HCMV DNA. To examine the role of HCMV infection in HCV spontaneous resolution, two groups of HCV patients, group 1) chronic HCV infection (positive HCV RNA and positive IgG antibodies) vs group 2) spontaneous resolution (negative HCV RNA and positive IgG antibodies) were compared. The percentages of positive CMV IgG and IgM results is higher in chronic HCV patient than those in spontaneously cleared HCV patients and the difference is highly statistically significant (P value < 0.001). Also, there is a general trend towards elevated levels of CMV IgG antibodies in HCV chronic patients than those in spontaneously cleared HCV patients (P value < 0.02). HCMV DNA detection in group 1 was more than twice the value observed in group 2 (38% vs 14.3%, P value < 0.001). Moreover, levels of liver enzymes were significantly higher in HCV RNA positive cases co-infected with HCMV DNA than HCMV negative cases (P value < 0.001). The results indicate the role of HCMV in the liver pathogenesis. We conclude that chronic HCV patients co-infected with HCMV infection can be regarded as high risk groups for liver disease progression where they should be monitored for the long term outcome of the disease.
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Affiliation(s)
- Ashraf Tabll
- Department of Microbial Biotechnology, National Research Center, Giza, Egypt.
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24
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Tabll A, Shoman S, Ghanem H, Nabil M, El Din NGB, El Awady MK. Assessment of human cytomegalovirus co-infection in Egyptian chronic HCV patients. Virol J 2011; 8:343. [PMID: 21740595 PMCID: PMC3145597 DOI: 10.1186/1743-422x-8-343] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 07/10/2011] [Indexed: 02/07/2023] Open
Abstract
Human cytomegalovirus (HCMV) is the most common cause of severe morbidity and mortality in immune- compromised individuals. This study was conducted to determine the incidence of HCMV infection in HCV patients who either spontaneously cleared the virus or progressed to chronic HCV infection. The study included a total of eighty four cases (48 females and 36 males) that were referred to blood banks for blood donation with an age range of 18-64 years (mean age 37.62 ± 10.03 years). Hepatitis C virus RNA and HCMV DNA were detected in sera by RT-nested PCR and nested PCR respectively in all subjects. Immunoglobulin G levels for HCV and HCMV were determined. Besides, IgM antibodies for HCMV infection were also determined in subjects' sera. Fifty three out of 84 cases (63%) were positive for HCV-RNA while 31 (37%) cases had negative HCV RNA. Forty six (87%) and 13 (25%) cases out of 53 HCV RNA positive patients were positive for HCMV IgG and IgM antibodies respectively. While 20 of 53 cases (38%) had detectable HCMV DNA. To examine the role of HCMV infection in HCV spontaneous resolution, two groups of HCV patients, group 1) chronic HCV infection (positive HCV RNA and positive IgG antibodies) vs group 2) spontaneous resolution (negative HCV RNA and positive IgG antibodies) were compared. The percentages of positive CMV IgG and IgM results is higher in chronic HCV patient than those in spontaneously cleared HCV patients and the difference is highly statistically significant (P value < 0.001). Also, there is a general trend towards elevated levels of CMV IgG antibodies in HCV chronic patients than those in spontaneously cleared HCV patients (P value < 0.02). HCMV DNA detection in group 1 was more than twice the value observed in group 2 (38% vs 14.3%, P value < 0.001). Moreover, levels of liver enzymes were significantly higher in HCV RNA positive cases co-infected with HCMV DNA than HCMV negative cases (P value < 0.001). The results indicate the role of HCMV in the liver pathogenesis. We conclude that chronic HCV patients co-infected with HCMV infection can be regarded as high risk groups for liver disease progression where they should be monitored for the long term outcome of the disease.
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Affiliation(s)
- Ashraf Tabll
- Department of Microbial Biotechnology, National Research Center, Giza, Egypt
| | - Sahar Shoman
- Department of Microbiology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hussam Ghanem
- Department of Microbiology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohamed Nabil
- Department of Microbiology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Noha G Bader El Din
- Department of Microbial Biotechnology, National Research Center, Giza, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, National Research Center, Giza, Egypt
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25
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Lee SO, Razonable RR. Current concepts on cytomegalovirus infection after liver transplantation. World J Hepatol 2010; 2:325-36. [PMID: 21161017 PMCID: PMC2998977 DOI: 10.4254/wjh.v2.i9.325] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Revised: 09/03/2010] [Accepted: 09/10/2010] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) is the most common viral pathogen that negatively impacts on the outcome of liver transplantation. CMV cause febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted allograft. In addition, CMV has been significantly associated with an increased predisposition to 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 on outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is regarded as an essential component to the medical management of liver transplant patients. Two recent 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 at least in one study, such occurrence of late-onset primary CMV disease was significantly associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention are needed, and aggressive treatment of CMV infection and disease should be pursued. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, one should also reduce the degree of immunosuppression. In one recent controlled clinical trial, valganciclovir was found to be as effective and safe as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. In this article, the authors review the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.
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Affiliation(s)
- Sang-Oh Lee
- Sang-Oh Lee, Division of Infectious Diseases, College of Medicine, Mayo Clinic, Rochester, MN 55905, United States
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26
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Kim JE, Oh SH, Kim KM, Choi BH, Kim DY, Cho HR, Lee YJ, Rhee KW, Park SJ, Lee YJ, Lee SG. Infections after living donor liver transplantation in children. J Korean Med Sci 2010; 25:527-31. [PMID: 20357992 PMCID: PMC2844587 DOI: 10.3346/jkms.2010.25.4.527] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Accepted: 07/27/2009] [Indexed: 11/20/2022] Open
Abstract
The aim of this study was to evaluate the infectious complications after living donor liver transplantation (LDLT) in children. We enrolled 95 children (38 boys and 57 girls) who underwent LDLT from 1994 to 2004. The median age was 22 months (range, 6 months to 15 yr). We retrospectively investigated the proven episodes of bacterial, viral, and fungal infection. There occurred 150 infections in 67 (70%) of 95 patients (1.49 infections/patient); 74 in 43 patients were bacterial, 2 in 2 were fungal, and 74 in 42 were viral. The most common sites of bacterial infection were the bloodstream (33%) and abdomen (25%). Most of the bacterial infections occurred within the first month after LDLT. Bacterial and fungal infections did not result in any deaths. The most common causes of viral infection were Epstein-Barr virus in 37 patients and cytomegalovirus in 18. Seven of the 14 deaths after LDLT were associated with viral infection. Our study suggests that infection is one of the important causes of morbidity and mortality after LDLT. Especially careful monitoring and management of viral infections is crucial for improving the outcome of LDLT in children.
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Affiliation(s)
- Jeong Eun Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
- Department of Pediatrics, Jung-Gu Community Health Center, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Bo Hwa Choi
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
- Department of Pediatrics, Yosuseongsim General Hospital, Yosu, Korea
| | - Dae Yeon Kim
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung Rae Cho
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeoun Joo Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kang Won Rhee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Seong Jong Park
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Joo Lee
- Division of Hepato-Biliary and Pancreas Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Gyu Lee
- Division of Hepato-Biliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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27
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Early and Delayed Onset Cytomegalovirus Infection of Liver Transplant Recipients in Endemic Areas. Transplant Proc 2010; 42:884-9. [DOI: 10.1016/j.transproceed.2010.02.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Lautenschlager I. CMV infection, diagnosis and antiviral strategies after liver transplantation. Transpl Int 2009; 22:1031-40. [PMID: 19619175 DOI: 10.1111/j.1432-2277.2009.00907.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Cytomegalovirus (CMV) is a significant pathogen complicating the post-transplant course of organ recipients. In liver transplant patients, the febrile clinical illness caused by CMV may be associated with end-organ disease, such as hepatitis or infection of the gastrointestinal tract. In addition to direct effects, CMV may have indirect effects including the risk of other infections or graft rejection. Recently, major advances in the management of CMV infection have been achieved through the development of new diagnostic techniques and antiviral strategies to prevent CMV disease. Quantitative nucleic acid testing to monitor viral load is now commonly used to diagnose and guide the treatment of CMV infections. The standardization of the testing, however, needs to be improved. There are two main strategies to prevent CMV disease after liver transplantation: prophylaxis and pre-emptive therapy. Both strategies are effective, but also have disadvantages. The disadvantages of prophylaxis include prolonged drug exposure, the development of resistance and, most of all, the development of delayed and late-onset CMV disease. On the other hand, the pre-emptive strategy is based on frequent laboratory monitoring of viral loads, and some patients may develop symptomatic infection before the diagnosis of CMV. This overview summarizes the current status of CMV in liver transplantation.
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Affiliation(s)
- Irmeli Lautenschlager
- Transplant Unit Research Laboratory, Transplantation and Liver Surgery Clinic, and Department of Virology, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.
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29
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Colmenero JDD, Castón JJ, Torre-Cisneros J. Fiebre, disnea e infiltrados pulmonares en una mujer de 50 años en tratamiento inmunodepresor. Med Clin (Barc) 2009; 132:638-44. [DOI: 10.1016/j.medcli.2008.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2008] [Accepted: 10/08/2008] [Indexed: 11/30/2022]
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30
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Razonable RR. Cytomegalovirus infection after liver transplantation: Current concepts and challenges. World J Gastroenterol 2008; 14:4849-60. [PMID: 18756591 PMCID: PMC2739936 DOI: 10.3748/wjg.14.4849] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is 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. Risk factors for CMV disease are often interrelated, and include CMV D+/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.
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31
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Egli A, Bergamin O, Müllhaupt B, Seebach J, Mueller N, Hirsch H. Cytomegalovirus-associated chorioretinitis after liver transplantation: case report and review of the literature. Transpl Infect Dis 2008; 10:27-43. [DOI: 10.1111/j.1399-3062.2007.00285.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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32
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Affiliation(s)
- Pierre Deltenre
- Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
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Ljungman P. Risk of cytomegalovirus transmission by blood products to immunocompromised patients and means for reduction. Br J Haematol 2004; 125:107-16. [PMID: 15059132 DOI: 10.1111/j.1365-2141.2004.04845.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Per Ljungman
- Department of Hematology, Huddinge University Hospital, Karolinska Institutet, SE-14186 Stockholm, Sweden.
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Fang F, Nie X, Li G. A model system of primary murine hepatocytes infected by murine cytomegalovirus. JOURNAL OF TONGJI MEDICAL UNIVERSITY = TONG JI YI KE DA XUE XUE BAO 2003; 19:185-9. [PMID: 12840890 DOI: 10.1007/bf02887730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In order to establish a model system of the murine hepatocyte infection by murine cytomegalovirus (MCMV), the primary cultured murine hepatocytes were obtained in a modified low-serum medium system by a non-perfusion method, and then infected by Smith strain MCMV. Infected hepatocytes showed characteristic cytopathic effect (CPE) at 30 h after infection, in which a large number of viral particles was found and ultrastructures were destroyed (as revealed by disappearance of bile canalicula and organelles) under the electron microscope and MCMV immediate-early genes were detected by in situ hybridization. Meanwhile, infected cells produced albumin significantly less than corresponding uninfected controls. On the contrary, uninfected controls simultaneously cultured under the same conditions showed normal function and ultrastructure (glycogen rosettes, bile canalicula, wheel-like mitochondria and well-developed rough and smooth endoplasmic reticula). These results demonstrated that a model system of primary cultured murine hepatocytes infected by MCMV was successfully set up.
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Affiliation(s)
- F Fang
- Department of Pediatrics, Tongji Hospital, Tongji Medical University, Wuhan 430030
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35
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Lautenschlager I, Höckerstedt K, Taskinen E. Histologic findings associated with CMV infection in liver transplantation. Transplant Proc 2003; 35:819. [PMID: 12644152 DOI: 10.1016/s0041-1345(03)00084-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- I Lautenschlager
- Department of Virology, Helsinki University and Helsinki University Central Hospital, Helsinki, Finland.
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36
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Seehofer D, Rayes N, Tullius SG, Schmidt CA, Neumann UP, Radke C, Settmacher U, Müller AR, Steinmüller T, Neuhaus P. CMV hepatitis after liver transplantation: incidence, clinical course, and long-term follow-up. Liver Transpl 2002; 8:1138-46. [PMID: 12474153 DOI: 10.1053/jlts.2002.36732] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cytomegalovirus (CMV) hepatitis is described as the most frequent manifestation of CMV tissue invasive disease after liver transplantation. Its correlation with HLA-matching, hepatic artery thrombosis, and chronic rejection is still controversial. Risk factors, incidence, clinical course, and complications of CMV hepatitis were retrospectively analyzed in a 12-year series of 1,146 consecutive liver transplantations in 1,054 patients. All patients received only low-dose acyclovir but no gancyclovir prophylaxis. CMV infection was diagnosed by viral culture, pp65 antigenemia, or by polymerase chain reaction (PCR). CMV hepatitis was proven by liver biopsy. Treatment of CMV disease consisted of intravenous ganciclovir for a minimum of 14 days. Long-term follow-up of patients included monthly routine laboratory values and routine liver biopsies 1, 3 and 5 years after transplantation. CMV hepatitis was a rare event after liver transplantation, with a total incidence of 2.1% (24 cases). It was significantly more frequent in CMV seronegative (5.2%) than in seropositive recipients (0.7%). The leading indication in patients with CMV hepatitis was HCV cirrhosis (n = 8). The maximum number of pp65 positive white blood cells was 82 +/- 23 per 10,000 cells. Most courses manifested as isolated hepatitis; only 2 patients had disseminated disease. Nine of 24 patients had received OKT3 monoclonal antibodies because of steroid-resistant rejection before CMV hepatitis. In seronegative patients with CMV hepatitis, 71% revealed 1 or 2 HLA DR matches, in contrast to 32% in patients without CMV hepatitis. One-, 3-, and 5-year graft survival was 78%, 65%, and 59% in patients with CMV hepatitis compared with 88%, 81%, and 79% in patients without. Chronic rejection was observed in one patient, but already before onset of CMV hepatitis. Beneath D+R-constellation and OKT3 treatment as risk factors, HLA DR-matched grafts and HCV seem to favor manifestation of CMV hepatitis after liver transplantation. Long-term complications of CMV hepatitis were not observed, and especially no correlation with chronic rejection was found.
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Affiliation(s)
- Daniel Seehofer
- Department of General, Visceral, and Transplant Surgery, Charité Campus Virchow, Humboldt University of Berlin, Berlin, Germany.
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Kano H, Mizuta K, Sakakihara Y, Kato H, Miki Y, Shibuya N, Saito M, Narita M, Kawarasaki H, Igarashi T, Hashizume K, Iwata T. Efficacy and safety of immunization for pre- and post- liver transplant children. Transplantation 2002; 74:543-50. [PMID: 12352917 DOI: 10.1097/00007890-200208270-00020] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Infection is a serious complication after liver transplantation. Immunization is one means of controlling infections. The objective of this study was to investigate the efficacy and safety of simultaneous administration of several vaccines before transplantation and the efficacy and safety of administration under immunosuppressive conditions after transplantation. METHODS Fifty-eight patients who underwent living-related liver transplantation between April 1994 and March 2000 were included in this study. Simultaneous administration of a maximum of six vaccines was performed in a short period of time before transplantation. We also readministered vaccines to 15 patients with waning antibody titers after transplantation from June 1999. We investigated whether patients could seroconvert for measles, rubella, mumps, and varicella after immunization and how long antibody titers could be retained by measuring them several times throughout the period before and after transplantation. We also examined side effects caused by immunization. RESULTS The rates of seroconversion against measles, rubella, mumps, and varicella after the pretransplantation vaccination were 82%, 100%, 90%, and 95%, respectively. The rates of reseroconversion against measles, rubella, mumps, and varicella after the posttransplantation revaccination were 85%, 100%, 100%, and 71%, respectively. Although antibody titers against these viruses generally waned with time, no patient exhibited any serious illness or side effects. CONCLUSION Although 12 of 58 patients (21%) had an infection, pretransplantation immunization was effective to prevent serious illness, especially for the 6 months after transplantation. Posttransplantation live-vaccine administration under immunosuppressive conditions is effective and safe.
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Affiliation(s)
- Hirotsugu Kano
- Department of Pediatrics, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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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; 56:341-8. [PMID: 11881318 DOI: 10.1179/acb.2001.051] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The differential diagnosis of hepatic fibrin-ring granulomas includes infective agents (Coxiella burneti, CMV, EBV,....), hypersensitivity to medication (allopurinol) and malignancy. METHODS During a period of 6 months, four patients presented at our university hospital with a similar clinical picture of fever and abnormal liver tests, and fibrin-ring granulomas on liver biopsy. Clinical course, laboratory and imaging findings, and histopathological features were compared. RESULTS Clinical manifestations, and laboratory and imaging findings were similar. Histopathological assessment of the hepatic fibrin-ring granulomas appeared not to be helpful in identifying the causative agent. Other histopathological features (e.g. sinusoidal rows of lymphocytes, eosinophilic polymorphonuclear infiltrate) were suggestive for the causative agent, yet conclusive identification was obtained by either serology (Q fever, CMV, EBV), or by exclusion with concomitant stop of medication (allopurinol). CONCLUSIONS In the differential diagnosis of hepatic fibrin-ring granulomas, serologic titers remain the determining factor, since an infective agent is the most common cause. When hepatic fibrin-ring granulomas are present, other histopathological features may be helpful in making the differential diagnosis.
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Affiliation(s)
- M Tjwa
- Dienst Lever, Galwegen- en Pancreasaandoeningen, Universitair Ziekenhuis Gasthuisberg, UZ GHB Herestraat 49 3000, Leuven, België Katholieke Universiteit Leuven
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Abstract
1. Lifelong monitoring of graft function, immunosuppressive levels, and screening for drug toxicity is required in all liver recipients. 2. Late hepatic allograft dysfunction is common and is caused by a variety of etiologies including rejection, infection, biliary/vascular abnormalities, recurrence of disease, and drug hepatotoxicity. 3. In all patients with late hepatic allograft dysfunction, liver biopsy should be performed to assess for the presence of rejection, and to thus avoid excessive use of bolus corticosteroid therapy and guide appropriate immunosuppressive management. 4. Recurrence of disease is the most common cause of late hepatic allograft dysfunction. 5. Hepatitis C universally reinfects the hepatic allograft, and is associated with decreased patient and graft survival and leads to the recurrence of cirrhosis in 28% of patients within 5 years of transplantation. 6. Major advances have been made in preventing recurrence of hepatitis B by the use of hepatitis B immune globulin in combination with lamivudine therapy. 7. Autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis have a recurrence rate of approximately 20% to 30%. 8. In patients developing recurrence of autoimmune hepatitis, steroid withdrawal is the most common cause. 9. Recurrent hepatocellular cancer can be markedly reduced if strict guidelines are adhered to in selecting patients. 10. Drug hepatotoxicity must always be considered in the differential diagnosis of late hepatic allograft dysfunction.
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Affiliation(s)
- R H Wiesner
- Mayo Clinic Liver Transplant Center, Rochester, MN 55905, USA.
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40
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Benz C, Reusch U, Muranyi W, Brune W, Atalay R, Hengel H. Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus. J Gen Virol 2001; 82:2061-2070. [PMID: 11514715 DOI: 10.1099/0022-1317-82-9-2061] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Liver and intestinal epithelial cells are a major target of infection by cytomegaloviruses (CMV), causing severe disease in affected organs of immunocompromised patients. CMV downregulates major histocompatibility complex class I (MHC-I) molecule expression in fibroblasts in order to avoid lysis by CD8(+) cytotoxic T lymphocytes. However, MHC-I expression in human cytomegalovirus (HCMV)-infected hepatic tissue was reported to be increased. As it is unclear at present whether HCMV affects MHC-I expression in epithelial cells, new cell culture models for HCMV infection of differentiated hepatobiliary cell lines were established. HCMV immediate early gene expression was achieved in 60 to 95% of cells. Progression of the HCMV replication cycle differed from prototypic infection of fibroblasts, since structural early and late proteins were produced at low levels and HCMV progeny yielded much lower titres in hepatobiliary cells. In contrast, HCMV glycoproteins, gpUS2, gpUS3, gpUS6 and gpUS11, that downregulate MHC-I expression were synthesized with temporal kinetics and in a similar quantity to that seen in fibroblasts. As a result, HCMV infection led to a drastic and selective downregulation of MHC-I expression in epithelial cells and was uniformly observed irrespective of the hepatic or biliary origin of the cells. The new models document for the first time a stealth function of HCMV in epithelial cells and indicate that the downregulation of MHC-I expression by HCMV can occur in the virtual absence of virus replication.
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Affiliation(s)
- Christine Benz
- Max von Pettenkofer-Institut, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany1
| | - Uwe Reusch
- Max von Pettenkofer-Institut, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany1
| | - Walter Muranyi
- Max von Pettenkofer-Institut, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany1
| | - Wolfram Brune
- Max von Pettenkofer-Institut, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany1
| | - Ramazan Atalay
- Max von Pettenkofer-Institut, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany1
| | - Hartmut Hengel
- Max von Pettenkofer-Institut, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany1
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Piiparinen H, Höckerstedt K, Grönhagen-Riska C, Lappalainen M, Suni J, Lautenschlager I. Comparison of plasma polymerase chain reaction and pp65-antigenemia assay in the quantification of cytomegalovirus in liver and kidney transplant patients. J Clin Virol 2001; 22:111-6. [PMID: 11418358 DOI: 10.1016/s1386-6532(01)00173-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is a significant problem in transplantation. The antiviral treatment is based on the clinical symptoms and the rapid laboratory diagnosis. Although polymerase chain reaction (PCR) methods have already been widely used, the clinical correlation of the findings is not clear. OBJECTIVE The objective of this study was to investigate the usefulness of a quantitative plasma PCR test and compare it with the pp65-antigenemia test in the detection of clinically significant CMV infections in liver and kidney transplant patients. STUDY DESIGN The clinical material consisted of 253 consecutive blood samples was tested using a quantitative polymerase chain reaction test, Cobas Amplicor CMV Monitor (Roche) and pp65 antigenemia assay. Plasma was used for PCR and leucocytes were used for the antigenemia test. RESULTS CMV was detected in 89 out of 253 blood samples by one or both methods. PCR detected 78 (range 274-165000 copies/ml) and pp65 antigenemia test 79 (range 1-1500 positive cells/50000) of the positive findings. The sensitivity and specificity of PCR test was 86 and 94%, respectively. The PCR detected all clinically significant CMV infections (>10 positive cells in pp65 test) and infections which required antiviral treatment. In addition, the correlation between the two tests was almost linear. CONCLUSIONS The quantitative PCR appears to be a suitable alternative to diagnose and monitor CMV infections in transplant patients.
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Affiliation(s)
- H Piiparinen
- Department of Virology, Helsinki University Central Hospital, Haartmaninkatu 3, FIN-00290, Helsinki, Finland.
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42
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Martelius TJ, Blok MJ, Inkinen KA, Loginov RJ, Höckerstedt KA, Bruggeman CA, Lautenschlager IT. Cytomegalovirus infection, viral DNA, and immediate early-1 gene expression in rejecting rat liver allografts. Transplantation 2001; 71:1257-61. [PMID: 11397959 DOI: 10.1097/00007890-200105150-00013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection has been linked to acute and chronic rejection. We have previously shown that concomitant rat cytomegalovirus (RCMV) infection increases portal inflammation and bile duct destruction in rejecting rat liver allografts. Many of the pro-inflammatory effects of CMV have been attributed to the immediate early (IE) proteins of CMV. We wanted to investigate whether RCMV and IE-1 gene expression persist in the liver graft in our model. METHODS Liver transplantations were performed from PVG (RT1c) into BN (RT1n) rats. One day after transplantation, the rats were infected with RCMV. No immunosuppression was given. The graft infection was studied by viral culture, immunofluorescence, DNA in situ hybridization and RT-PCR for the detection of IE-1 mRNA at various time points. RESULTS RCMV caused an active infection from 5 days to 2 weeks after transplantation, during which infectious virus was found in the graft. Thereafter the cultures were negative. RCMV antigens and DNA were found in hepatocytes, endothelial, inflammatory, and bile duct cells during the active infection. At 4 weeks, RCMV DNA positive hepatocytes, endothelial, inflamma tory, and bile duct cells could still be found, but in much smaller quantities. IE-1 mRNA expression was, however, only detected during the active infection, not at 4 weeks postinfection. CONCLUSIONS RCMV IE-1 expression does not persist in the graft after the active infection, although some viral DNA can be detected in the graft up to 4 weeks. In our model, the CMV-induced increase in graft damage does not seem to require the continued expression of IE-1.
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Affiliation(s)
- T J Martelius
- Department of Surgery, Helsinki University Hospital, Finland
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Lautenschlager I, Höckerstedt K, Salmela K. Good and impaired response to ganciclovir treatment of severe CMV infections in liver transplant recipients. Transpl Int 2001; 7 Suppl 1:S232-4. [PMID: 11271212 DOI: 10.1111/j.1432-2277.1994.tb01355.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
In this study we investigated good and impaired clinical responses to ganciclovir treatment of severe CMV disease in 23 adult liver transplant patients. CMV episodes were diagnosed by direct immunodetection of CMV-specific antigens in blood leukocytes and by viral cultures. The patients were monitored weekly for CMV antigenemia during the antiviral treatment. Sixteen out of 23 patients recovered from CMV episodes with the standard ganciclovir therapy of 2 weeks. Seven patients demonstrated an impaired response to ganciclovir and had to be treated for longer than 2 weeks (29 +/- 9 days). The patients with an impaired response to ganciclovir also demonstrated higher CMV antigenemia levels compared to those with good a response, and all still had antigenemia after 2 weeks' therapy. Thus, most severe CMV infections in liver transplant patients subsided with ganciclovir treatment of 2 weeks, but impaired responses also occurred and patients had to be treated for several weeks with ganciclovir before they recovered from CMV.
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44
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Teixeira R, Pastacaldi S, Davies S, Dhillon AP, Emery VC, Rolles K, Davidson B, Patch D, Burroughs AK. The influence of cytomegalovirus viraemia on the outcome of recurrent hepatitis C after liver transplantation. Transplantation 2000; 70:1454-8. [PMID: 11118089 DOI: 10.1097/00007890-200011270-00010] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Several interrelated host and hepatitis C virus (HCV) associated factors have been proposed to explain the variable outcomes in HCV recurrence. Recent evidence suggests that cytomegalovirus (CMV) infection not only is co-factor in progression of HCV recurrence but may precipitate allograft rejection. We investigated whether short-term CMV viremia influences HCV recurrence, the number and grade of acute rejection episodes, and the histological course of HCV recurrence during the first year after orthotopic liver transplantation (OLT) for HCV-related cirrhosis. METHODS A cohort of 39 patients transplanted for cirrhosis HCV-related was analyzed. Patients were evaluated twice weekly for CMV infection by a blood polymerase chain reaction (PCR) assay. Triple therapy with cyclosporine or tacrolimus, azathioprine and prednisolone was the initial immunosuppressive regimen. Preemptive treatment with ganciclovir was started when two consecutive PCRs for CMV were positive. Liver biopsies were performed on day 7 after OLT or when indicated. A 3-day IV 1 g methilprednisolone was given to patients with moderate or severe rejection. Ishak's score was used to grade inflammation and to stage fibrosis. RESULTS Neither CMV viremia nor CMV disease after OLT for HCV-related cirrhosis adversely influenced the incidence and grade of acute rejection episodes nor the histological outcome of post transplant HCV recurrence, during the first year after liver transplantation. CONCLUSION CMV viremia as detected by PCR does not affect the progression of HCV recurrence in liver grafts.
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Affiliation(s)
- R Teixeira
- Department of Histopathology, Royal Free Hospital, London, UK
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45
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Bai X, Rogers BB, Harkins PC, Sommerauer J, Squires R, Rotondo K, Quan A, Dawson DB, Scheuermann RH. Predictive value of quantitative PCR-based viral burden analysis for eight human herpesviruses in pediatric solid organ transplant patients. J Mol Diagn 2000; 2:191-201. [PMID: 11232109 PMCID: PMC1906918 DOI: 10.1016/s1525-1578(10)60637-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Human herpesviruses can cause significant morbidity and mortality in pediatric solid organ transplant recipients. It was hypothesized that viral burden quantification by polymerase chain reaction using an internal calibration standard could aid in distinguishing between viral disease and latency. Here we report the results of a 2-year prospective study of 27 pediatric solid organ (liver, kidney, or heart) transplant recipients in which multiple samples were analyzed for levels of all eight human herpesviruses by internal calibration standard-polymerase chain reaction. Herpes simplex viruses 1 and 2, varicella-zoster virus, and Kaposi's sarcoma-associated herpesvirus were not detected in any of these samples. Human herpesvirus types 6 and 7 were detected in half of the patients, but were present at low levels, similar to those found in reference populations. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were detected in 89% and 56% of the patients, respectively. Viral burden analysis suggested distinct patient populations for CMV, with a natural cutoff of 10,000 viral targets/ml blood strongly associated with disease. In some cases, a dramatic increase in CMV levels preceded clinical evidence of disease by several weeks. EBV viral burden was relatively high in the only patient presenting with an EBV syndrome. However, two other patients without evidence of EBV disease had single samples with high EBV burden. Rapid reduction in both EBV and CMV burden occurred with antiviral treatment. These data suggest that viral burden analysis using internal calibration standard-polymerase chain reaction for CMV, and possibly other herpesviruses, is an effective method for monitoring pediatric transplant patients for significant herpesvirus infection and response to therapy.
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Affiliation(s)
- X Bai
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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46
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Castiglione F, Del Vecchio Blanco G, Rispo A, Cozzolino A, Di Girolamo E, Cappuccio D, Mazzacca G. Hepatitis related to cytomegalovirus infection in two patients with Crohn's disease treated with azathioprine. Dig Liver Dis 2000; 32:626-9. [PMID: 11142564 DOI: 10.1016/s1590-8658(00)80848-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Azathioprine-related side-effects occur in about 15% of treated patients. Liver toxicity is a rare complication of this drug, but is considered, in most cases, a contraindication to the continuation of treatment. However, abnormal liver tests may occur in patients under azathioprine treatment also due to infections. The distinction between toxic and infective causes of abnormal liver tests is important in order to identify patients that can be rechallenged with the drug. Cytomegalovirus infection is common in immunosuppressed transplant recipients, while the incidence is lower in patients with inflammatory bowel disease treated with immunosuppressive drugs. To our knowledge, only 2 cases of cytomegalovirus hepatitis occurring during azathioprine treatment for Crohn's disease had been reported so far. Here, we describe two patients who experienced mild hepatitis associated with the onset of cytomegalovirus infection during azathioprine treatment. The infection was documented by the appearance of IgM anti cytomegalovirus. Both cases were self-limiting. In one of the 2 patients, azathioprine was given again after resolution of the hepatitis with good control of Crohn's disease and without other complications. We also retrospectively evaluated the incidence of liver abnormalities assessed by blood tests in 58 consecutive patients with Crohn's disease treated with azathioprine at our institution. Abnormal results were obtained in 8 out of these 58 patients, requiring discontinuation of the drug in 3 patients, two of whom were the cytomegalovirus cases described above.
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Affiliation(s)
- F Castiglione
- Division of Gastroenterology, Medical School, University Federico II, Naples, Italy.
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47
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Cebulla CM, Miller DM, Knight DA, Briggs BR, McGaughy V, Sedmak DD. Cytomegalovirus induces sialyl Lewis(x) and Lewis(x) on human endothelial cells. Transplantation 2000; 69:1202-9. [PMID: 10762227 DOI: 10.1097/00007890-200003270-00027] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is the primary viral cause of complications in transplant recipients. We sought to understand the mechanisms of its dissemination and induction of vascular disease, which may lead to transplant complications. Sialyl Lewis(x) (sLe(x)) and Lewis(x) (Le(x)) are known for their roles in mediating cell adhesion and as tumor-associated carbohydrate antigens. Herein we explore whether CMV induces surface expression of these important molecules in endothelial cells (EC). METHODS Flow cytometry was used to detect surface expression of sLe(x) and Le(x) on CMV-infected human umbilical vein endothelial cells (HUVEC), with or without ultraviolet inactivation of the virus. To elucidate mechanisms of CMV-mediated induction, mRNA coding for predominant HUVEC sialyltransferases (ST) and fucosyltransferases (FT), key enzymes in sLe(x) and Le(x) synthesis, was analyzed by Northern blot. Dual immunohistochemical staining for sLe(x) and Le(x) expression of human colon and placental tissue was performed to investigate in vivo relevance. RESULTS sLe(x) expression on CMV-infected HUVEC was strongly up-regulated by 8 days after inoculation. Le(x) expression was detectable earlier and increased steadily over time. In contrast, ultraviolet-inactivated CMV did not induce expression of these molecules. Northern blot assays demonstrated higher levels of important EC glycosyltransferases ST-IV, FT-III, and FT-IV in CMV-infected EC. Finally, high levels of sLe(x) and Le(x) were expressed in CMV-infected EC in vivo. CONCLUSIONS Given the known biologic functions of sLe(x) and Le(x), we suggest that CMV induction of these molecules may have widespread consequences ranging from CMV dissemination to induction of CMV-associated vascular disease, including thrombosis.
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Affiliation(s)
- C M Cebulla
- Department of Pathology, The Ohio State University College of Medicine and Public Health, Columbus 43210, USA
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48
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Affiliation(s)
- P Sampathkumar
- Division of Infectious Disease, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA
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49
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Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 2000; 13:83-121, table of contents. [PMID: 10627493 PMCID: PMC88935 DOI: 10.1128/cmr.13.1.83] [Citation(s) in RCA: 118] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
In the past three decades since the inception of human organ transplantation, cytomegalovirus (CMV) has gained increasing clinical import because it is a common pathogen in the immunocompromised transplant recipient. Patients may suffer from severe manifestations of this infection along with the threat of potential fatality. Additionally, the dynamic evolution of immunosuppressive and antiviral agents has brought forth changes in the natural history of CMV infection and disease. Transplant physicians now face the daunting task of recognizing and managing the changing spectrum of CMV infection and its consequences in the organ recipient. For the microbiology laboratory, the emphasis has been geared toward the development of more sophisticated detection assays, including methods to detect emerging antiviral resistance. The discovery of novel antiviral chemotherapy is an important theme of clinical research. Investigations have also focused on preventative measures for CMV disease in the solid-organ transplant population. In all, while much has been achieved in the overall management of CMV infection, the current understanding of CMV pathogenesis and therapy still leaves much to be learned before success can be claimed.
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Affiliation(s)
- I G Sia
- Division of Infectious Diseases and Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
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Rosen HR, Corless CL, Rabkin J, Chou S. Association of cytomegalovirus genotype with graft rejection after liver transplantation. Transplantation 1998; 66:1627-31. [PMID: 9884250 DOI: 10.1097/00007890-199812270-00010] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The envelope glycoprotein gB of human cytomegalovirus (CMV) occurs as one of four main genotypes. Some previous studies have proposed a relationship of CMV gB genotype to the frequency of symptomatic infection and to clinical outcomes in both transplant and human immunodeficiency virus-infected populations. Our aim was to define the distribution of CMV gB genotypes and the impact on acute cellular rejection and graft/patient survival after orthotopic liver transplantation (OLT). METHODS Between October 1988 and December 1996, 325 patients underwent cyclosporine-based OLT at our center. CMV infection was surveyed prospectively and defined as viral isolation from blood or urine; 53 (16%) patients had detectable CMV. Isolates were genotyped by polymerase chain reaction amplification and restriction digest analysis. RESULTS The distribution of CMV genotypes was: gB1, 19 (36%) patients; gB2, 15 (28%) patients; gB3, 13 (24%) patients; and gB4, 4 (8%) patients. Two patients (4%) had mixed infection (1 + 3, 1 + 4). Age, preOLT diagnosis, use of ganciclovir prophylaxis, basal immunosuppression, mean number of HLA donor/recipient mismatches, and United Network of Organ Sharing status were comparable among patients with different genotypes. Patients with gBl had a significantly higher mean number of acute rejection episodes (1.52+0.30 vs. 0.67+0.22; P=0.027). However, there was no difference in rejection severity, including OKT3 usage or FK506 conversion, or development of chronic rejection among patients with different genotypes. The gB genotype did not affect the development of symptomatic or tissue-invasive CMV disease, detected in 15 patients. Actuarial rates of patient (odds ratio [OR] 3.0; confidence interval [CI] 1.49-6.0) and graft (OR 2.57; CI 1.25-5.22) survival were significantly diminished in the group with CMV infection versus those without CMV (P<0.0001 for both), but there was no association with CMV genotype. CONCLUSIONS (1) Patients with CMV infection had significantly reduced patient and graft survival rates at 1 and 5 years after OLT as compared with OLT recipients without CMV infection. (2) CMV genotype gB1 was associated with a higher mean number of acute rejection episodes.
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Affiliation(s)
- H R Rosen
- Department of Medicine, Portland Veterans Affairs Medical Center and Oregon Health Sciences University, 97207, USA.
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