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Pellett Madan R, Hand J. Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13518. [PMID: 30844089 DOI: 10.1111/ctr.13518] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 02/26/2019] [Indexed: 12/17/2022]
Abstract
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV-6A, HHV-6B, HHV-7, and HHV-8 in the pre- and post-transplant period. The majority of HHV-6 (A and B) and HHV-7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV-6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV-6 and HHV-7 infection. The possibility of chromosomally integrated HHV-6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV-6 encephalitis and should be considered for other manifestations of disease. HHV-8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV-8 screening and monitoring may be indicated to prevent disease. Treatment of HHV-8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV-8 infection has not yet been defined.
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Affiliation(s)
- Rebecca Pellett Madan
- Department of Pediatrics, New York University Langone School of Medicine, New York City, New York
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Clinical School, Ochsner Medical Center, The University of Queensland School of Medicine, New Orleans, Louisiana
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Abstract
Human herpesvirus 6 (HHV-6A and HHV-6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV-6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate histopathological effects of HHV-6 remains the gold standard for diagnosis of end-organ disease. HHV-6 reactivation may be restricted to the infected organ with no evidence of active infection in the blood. HHV-6 infections in liver transplant patients are mostly asymptomatic, but clinically significant tissue-invasive infections have been treated successfully with ganciclovir, foscarnet or cidofovir. Inherited chromosomally integrated HHV-6 (ciHHV-6), in either the recipient or the donor organ, may create confusion about systemic HHV-6 infection. Recipients with inherited ciHHV-6 may have an increased risk of opportunistic infection and graft rejection. This article reviews the current scientific data on the clinical effects, risk factors, pathogenesis, diagnosis and treatment of HHV-6 infections in liver transplant recipients.
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Affiliation(s)
| | - Irmeli Lautenschlager
- Department of Virology, Helsinki University Hospital, Helsinki University, Helsinki, Finland
| | - Raymund R Razonable
- Division of Infectious Diseases, Department of Medicine and the William J von Liebig Center for Transplantation and Clinical Regeneration, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Flor M Munoz
- Department of Pediatrics, Transplant Infectious Diseases, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
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Yadav SK, Saigal S, Choudhary NS, Saha S, Kumar N, Soin AS. Cytomegalovirus Infection in Liver Transplant Recipients: Current Approach to Diagnosis and Management. J Clin Exp Hepatol 2017; 7:144-151. [PMID: 28663679 PMCID: PMC5478971 DOI: 10.1016/j.jceh.2017.05.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 05/16/2017] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) infection is the most common viral infection in liver transplant recipients, affecting post-transplant patients and graft survival. Recent advances in diagnosis and management of CMV have led to marked reduction in incidence, severity, and its associated morbidity and mortality. CMV DNA assay is the most commonly used laboratory parameter to diagnose and monitor CMV infection. Current evidence suggests that both pre-emptive and universal prophylaxis approaches are equally justified in liver transplant recipients. Intravenous ganciclovir and oral valganciclovir are the most commonly used drugs for treatment of CMV disease. Most of the centre use valganciclovir prophylaxis for prevention of CMV disease in liver trasplant recipient. The aim of this article is to review the current standard of care for diagnosis and management of CMV disease in liver transplant recipients.
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Affiliation(s)
| | - Sanjiv Saigal
- Institute of Liver Transplantation and Regenerative Medicine and Dept of Microbiology, Medanta The Medicity, Gurugram, India
| | | | | | - Navin Kumar
- Institute of Liver Transplantation and Regenerative Medicine and Dept of Microbiology, Medanta The Medicity, Gurugram, India
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Impact of Cytomegalovirus Infection on Severe Hepatitis C Recurrence in Patients Undergoing Liver Transplantation. Transplantation 2016; 100:593-9. [PMID: 26371595 DOI: 10.1097/tp.0000000000000912] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The influence of cytomegalovirus (CMV) on recurrent hepatitis C virus (HCV) in liver grafts is controversial. Our aim was to investigate the association between CMV infection and disease and severe HCV recurrence (composite variable of presence of stage 3 to 4 fibrosis, need for retransplantation or death due to liver disease) in the first year after transplantation. METHODS An observational, prospective, multicenter study was performed. The CMV replication was monitored by determining CMV viral load weekly during hospitalization after transplantation, twice monthly in the first 3 months after discharge, and at each follow-up visit until month 12. Liver fibrosis was assessed histologically by liver biopsy or transient elastometry. Pretransplant, intraoperative, and posttransplant variables were recorded. Multiple logistic regression was performed to study the impact of CMV on severe HCV recurrence. RESULTS Ninety-eight patients were included. The CMV infection was detected in 48 patients (49%) in the first year posttransplant, of which 11 patients (22.9%) had CMV disease. Twenty-three patients (23.5%) had severe HCV recurrence. Of these, 17 (73.9%) developed stage 3 to 4 fibrosis, 4 (17.4%) died, and 2 (8.7%) underwent retransplantation. Only 7 of 12 (58.3%) seronegative recipients of a seropositive donor (positive donor/negative recipient [D+/R-]) received universal prophylaxis, and 10 of 12 (83.3%) D+/R- patients developed CMV replication. In the multivariate analysis, the presence of CMV D+/R- serodiscordance (odds ratio, 6.87; 95% confidence interval, 1.89-24.99; P = 0.003), and detection of a higher peak HCV viral load (odds ratio, 3.85; 95% confidence interval, 1.49-9.94; P = 0.005) were associated with severe HCV recurrence. CONCLUSIONS Our results support an association between CMV D+/R- serodiscordance and severe HCV recurrence in patients undergoing liver transplantation for HCV liver disease.
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Martin-Gandul C, Mueller NJ, Pascual M, Manuel O. The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation. Am J Transplant 2015; 15:3024-40. [PMID: 26474168 DOI: 10.1111/ajt.13486] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 07/14/2015] [Accepted: 08/06/2015] [Indexed: 01/25/2023]
Abstract
Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community-acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction.
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Affiliation(s)
- C Martin-Gandul
- Transplantation Center, University Hospital and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - N J Mueller
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - M Pascual
- Transplantation Center, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - O Manuel
- Transplantation Center, University Hospital and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
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Wiwanitkit V. Pityriasis rosea in chronic hepatitis C. Balkan Med J 2015; 31:368. [PMID: 25667797 DOI: 10.5152/balkanmedj.2014.14778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 09/24/2014] [Indexed: 11/22/2022] Open
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Grassi A, Ballardini G. Post-liver transplant hepatitis C virus recurrence: an unresolved thorny problem. World J Gastroenterol 2014; 20:11095-11115. [PMID: 25170198 PMCID: PMC4145752 DOI: 10.3748/wjg.v20.i32.11095] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related cirrhosis represents the leading cause of liver transplantation in developed, Western and Eastern countries. Unfortunately, liver transplantation does not cure recipient HCV infection: reinfection universally occurs and disease progression is faster after liver transplant. In this review we focus on what happens throughout the peri-transplant phase and in the first 6-12 mo after transplantation: during this crucial period a completely new balance between HCV, liver graft, the recipient's immune response and anti-rejection therapy is achieved that will deeply affect subsequent outcomes. Nearly all patients show an early graft reinfection, with HCV viremia reaching and exceeding pre-transplant levels; in this setting, histological assessment is essential to differentiate recurrent hepatitis C from acute or chronic rejection; however, differentiating the two patterns remains difficult. The host immune response (mainly cellular mediated) appears to be crucial both in the control of HCV infection and in the genesis of rejection, and it is also strongly influenced by immunosuppressive treatment. At present no clear immunosuppressive strategy could be strongly recommended in HCV-positive recipients to prevent HCV recurrence, even immunotherapy appears to be ineffective. Nonetheless it seems reasonable that episodes of rejection and over-immunosuppression are more likely to enhance the risk of HCV recurrence through immunological mechanisms. Both complete prevention of rejection and optimization of immunosuppression should represent the main goals towards reducing the rate of graft HCV reinfection. In conclusion, post-transplant HCV recurrence remains an unresolved, thorny problem because many factors remain obscure and need to be better determined.
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Abstract
PURPOSE OF REVIEW This article summarizes the current state of the epidemiology, diagnosis, and management of human herpesvirus 6 (HHV-6) infection after solid organ transplantation. RECENT FINDINGS HHV-6 reactivates commonly during the early weeks after solid organ transplantation. However, disease due to HHV-6 is uncommon and is manifested as a febrile illness associated with rash and tissue-invasive manifestations such as encephalitis, hepatitis, pneumonitis, and gastrointestinal disease. HHV-6 has also been indirectly associated with other opportunistic infections such as cytomegalovirus and fungal infections. Molecular tests such as PCR assays are preferred methods for the diagnosis of HHV-6 infection. Recent guideline from the American Society of Transplantation Infectious Disease Community of Practice does not recommend specific antiviral prophylaxis or preemptive therapy for HHV-6 infection. For established disease, intravenous ganciclovir and foscarnet are considered first-line agents. SUMMARY Infection due to HHV-6 is a common after transplantation, but clinical disease is rare. Nonetheless, this infection has been indirectly associated with poor allograft and patient survival after transplantation. No specific prevention strategy is recommended, but treatment of established HHV-6 disease consists of antiviral therapy with intravenous ganciclovir and/or foscarnet, and reduction in immunosuppression.
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New insights in recurrent HCV infection after liver transplantation. Clin Dev Immunol 2013; 2013:890517. [PMID: 23710205 PMCID: PMC3655463 DOI: 10.1155/2013/890517] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 03/17/2013] [Accepted: 03/31/2013] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) is a small-enveloped RNA virus belonging to the Flaviviridae family. Since first identified in 1989, HCV has been estimated to infect 170 million people worldwide. Mostly chronic hepatitis C virus has a uniform natural history, from liver cirrhosis to the development of hepatocellular carcinoma. The current therapy for HCV infection consists of a combination of Pegylated interferon and ribavirin. On the other hand, HCV-related liver disease is also the leading indication for liver transplantation. However, posttransplant HCV re-infection of the graft has been reported to be universal. Furthermore, the graft after HCV re-infection often results in accelerated progression to liver failure. In addition, treatment of recurrent HCV infection after liver transplantation is often compromised by enhanced adverse effects and limited efficacy of interferon-based therapies. Taken together, poor outcome after HCV re-infection, regardless of grafts or recipients, poses a major issue for the hepatologists and transplant surgeons. The aim of this paper is to review several specific aspects regarding HCV re-infection after transplant: risk factors, current therapeutics for HCV in different stages of liver transplantation, cellular function of HCV proteins, and molecular mechanisms of HCV entry. Hopefully, this paper will inspire new strategies and novel inhibitors against recurrent HCV infection after liver transplantation and greatly improve its overall outcome.
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Le J, Gantt S. Human herpesvirus 6, 7 and 8 in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:128-37. [PMID: 23465006 DOI: 10.1111/ajt.12106] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J Le
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
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Razonable RR. Human herpesviruses 6, 7 and 8 in solid organ transplant recipients. Am J Transplant 2013; 13 Suppl 3:67-77; quiz 77-8. [PMID: 23347215 DOI: 10.1111/ajt.12008] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Revised: 07/05/2012] [Accepted: 07/05/2012] [Indexed: 01/25/2023]
Abstract
Human herpesviruses (HHV) 6 and 7 are ubiquitous infections that reactivate commonly in transplant recipients. However, clinical diseases due to these viruses are reported only in 1% of solid organ transplant recipients. Fever, rash and bone marrow suppression are the most common manifestations, but symptoms of tissue invasive disease may be observed. Treatment of HHV-6 and HHV-7 disease includes antiviral therapy and cautious reduction in immunosuppression. HHV-8 is an oncogenic gamma-herpesvirus that causes Kaposi's sarcoma, Castleman's disease and primary effusion lymphomas in transplant recipients. Nonmalignant diseases such as bone marrow suppression and multiorgan failure have also been associated with HHV-8. Reduction in immunosuppression is the first line treatment of HHV-8 infection. Other alternatives for treatment, especially for HHV-8 diseases not responsive to immuno-minimization strategies, are surgery and chemotherapy. Sirolimus has been shown to be a beneficial component for the treatment of Kaposi's sarcoma and the role of antivirals for HHV-8 infection is being investigated.
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Affiliation(s)
- R R Razonable
- Division of Infectious Diseases, Department of Medicine, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Hasan Z, Mahmood F, Jamil B, Atkinson B, Mohammed M, Samreen A, Altaf L, Moatter T, Hewson R. Crimean-Congo hemorrhagic fever nosocomial infection in a immunosuppressed patient, Pakistan: Case report and virological investigation. J Med Virol 2012; 85:501-4. [DOI: 10.1002/jmv.23473] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2012] [Indexed: 11/10/2022]
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Grossi PA, Costa AN, Fehily D, Blumberg EA, Kuehnert MJ, Fishman JA, Ison MG, Lattes R, Kotton CN, Lilleri D, Kabanova A, Lanzavecchia A, Gerna G, Razonable RR, Comoli P, Zecca M, Basso S, Ginevri F, Grossi A, Schena FP, Rimola A, Burra P, De Martin E, Rodriguez-Castro KI, Fagiuoli S, Pasulo L, Bruno R, Andreone P, Loggi E, Arena F, Rossolini GM, Sganga G, Cozza V. Infections and organ transplantation: new challenges for prevention and treatment--a colloquium. Transplantation 2012; 93:S4-S39. [PMID: 22374265 DOI: 10.1097/tp.0b013e3182481347] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Paolo A Grossi
- Infectious Diseases Department, University of Insubria, Varese, ISMETT-UPMC Palermo, National Center for Transplantation, Rome, Italy.
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Lautenschlager I, Razonable RR. Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review. Transpl Int 2012; 25:493-502. [PMID: 22356254 DOI: 10.1111/j.1432-2277.2012.01443.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Human herpesvirus-6 (HHV-6), which comprises of HHV-6A and HHV-6B, is a common infection after solid organ transplantation. The rate of HHV-6 reactivation is high, although clinical disease is not common. Only 1% of transplant recipients will develop clinical illness associated with HHV-6 infection, and most are ascribable to HHV-6B. Fever, myelosuppression, and end-organ disease, including hepatitis and encephalitis, have been reported. HHV-6 has also been associated with various indirect effects, including a higher rate of CMV disease, acute and chronic graft rejection, and opportunistic infection such as invasive fungal disease. All-cause mortality is increased in solid organ transplant recipients with HHV-6 infection. HHV-6 is somewhat unique among human viruses because of its ability to integrate into the host chromosome. The clinical significance of chromosomally integrated HHV-6 is not yet defined, although a higher rate of bacterial infection and allograft rejection has been suggested. The diagnosis of HHV-6 is now commonly made using nucleic acid testing for HHV-6 DNA in clinical samples, but this can be difficult to interpret owing to the common nature of asymptomatic viral reactivation. Treatment of HHV-6 is indicated in established end-organ disease such as encephalitis. Foscarnet, ganciclovir, and cidofovir have been used for treatment.
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Affiliation(s)
- Irmeli Lautenschlager
- Department of Virology, Helsinki University Hospital, and Helsinki University, Helsinki, Finland.
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Human herpesvirus 6 in donor biopsies associated with the incidence of clinical cytomegalovirus disease and hepatitis C virus recurrence. Int J Infect Dis 2012; 16:e124-9. [DOI: 10.1016/j.ijid.2011.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 10/17/2011] [Accepted: 10/22/2011] [Indexed: 11/21/2022] Open
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Clinical Significance of Pretransplant Chromosomally Integrated Human Herpesvirus-6 in Liver Transplant Recipients. Transplantation 2011; 92:224-9. [DOI: 10.1097/tp.0b013e318222444a] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Razonable RR, Lautenschlager I. Impact of human herpes virus 6 in liver transplantation. World J Hepatol 2010; 2:345-53. [PMID: 21161019 PMCID: PMC2998978 DOI: 10.4254/wjh.v2.i9.345] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Revised: 07/14/2010] [Accepted: 07/21/2010] [Indexed: 02/06/2023] Open
Abstract
Human herpes virus 6 (HHV-6) infects > 95% of humans. Primary infection which occurs mostly during the first 2 years of life in the form of roseola infantum, non-specific febrile illness, or an asymptomatic illness, results in latency. Reactivation of latent HHV-6 is common after liver transplantation. Since the majority of human beings harbor the latent virus, HHV-6 infections after liver transplantation are most probably caused by endogenous reactivation or superinfection. In a minority of cases, primary HHV-6 infection may occur when an HHV-6-seronegative individual receives a liver allograft from an HHV-6-seropositive donor. The vast majority of HHV-6 infections after liver transplantation are asymptomatic. Only in a minority of cases, when HHV-6 causes a febrile illness associated with rash and myelosuppression, hepatitis, gastroenteritis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been implicated in a variety of indirect effects, such as allograft rejection and increased predisposition to and severity of other infections, including cytomegalovirus, hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach prevention after liver transplantation. Asymptomatic HHV-6 infection does not require antiviral treatment, while treatment of established HHV-6 disease is treated with intravenous ganciclovir, foscarnet, or cidofovir and this should be complemented by a reduction in immunosuppression.
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Affiliation(s)
- Raymund R Razonable
- Raymund R Razonable, Division of Infectious Diseases, Department of Medicine, and the William J von Liebig Transplant Center, College of Medicine, Mayo Clinic, Rochester, MN 55905, United States
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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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Ablashi DV, Devin CL, Yoshikawa T, Lautenschlager I, Luppi M, Kühl U, Komaroff AL. Review Part 3: Human herpesvirus-6 in multiple non-neurological diseases. J Med Virol 2010; 82:1903-10. [DOI: 10.1002/jmv.21860] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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Razonable RR, Zerr DM. HHV-6, HHV-7 and HHV-8 in solid organ transplant recipients. Am J Transplant 2009; 9 Suppl 4:S97-100. [PMID: 20070702 DOI: 10.1111/j.1600-6143.2009.02899_1.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- R R Razonable
- Division of Infectious Diseases, College of Medicine, Mayo Clinic, Rochester, MN, USA.
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Fazakas Á, Csire M, Berencsi G, Szepesi Á, Matolcsy A, Jakab L, karádi I, Várkonyi J. Multicentric plasmocytic Castleman's disease with polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes syndrome and coexistent human herpes virus-6 infection – a possible relationship. Leuk Lymphoma 2009; 50:1661-5. [DOI: 10.1080/10428190903162743] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Abstract
Human herpesvirus 6 (HHV-6) infections occur in > 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection (reactivation in the transplanted organ). In a minority of cases, however, primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus (CMV), hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir, or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.
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Humar A, Asberg A, Kumar D, Hartmann A, Moussa G, Jardine A, Rollag H, Mouas H, Gahlemann CG, Pescovitz MD. An assessment of herpesvirus co-infections in patients with CMV disease: correlation with clinical and virologic outcomes. Am J Transplant 2009; 9:374-81. [PMID: 19120074 DOI: 10.1111/j.1600-6143.2008.02501.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The effect of herpesvirus co-infections (HHV-6, HHV-7) on cytomegalovirus (CMV) disease and its response to therapy is unknown. We prospectively analyzed herpesvirus co-infections in transplant recipients with CMV disease. All patients received 3 weeks of antiviral therapy. Samples were collected at baseline (day 0) and then day 3, 7, 14 and 21 poststart of therapy. Viral load testing for CMV, HHV-6 and HHV-7 was done using quantitative PCR assays in 302 patients of whom 256 had documented symptomatic CMV viremia. In this subset, day 0 HHV-6 co-infection was present in 23/253 (9.1%) and HHV-7 in 17/253 (6.7%). Including those positive at any time point raised the prevalence to 79/256 (30.9%) for HHV-6 and 75/256 (29.3%) for HHV-7. Viral co-infection did not influence the response of CMV disease to antiviral therapy. Baseline CMV viral loads, time to eradication and risk of recurrence were similar in patients with and without HHV-6 or HHV-7 co-infection. Ganciclovir and valganciclovir had no clear effect on HHV-6 and HHV-7 viremia. In conclusion, herpesvirus co-infections are common in patients with CMV disease but with standard antiviral therapy, no clear clinical effects are discernable. Routine monitoring for viral co-infection in patients with CMV disease is not indicated.
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Affiliation(s)
- A Humar
- Department of Medicine, University of Alberta, Edmonton, AB, Canada.
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Emerging Viruses in Transplantation: There Is More to Infection After Transplant Than CMV and EBV. Transplantation 2008; 86:1327-39. [DOI: 10.1097/tp.0b013e31818b6548] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Hlava N, Niemann CU, Gropper MA, Melcher ML. Postoperative infectious complications of abdominal solid organ transplantation. J Intensive Care Med 2008; 24:3-17. [PMID: 19017663 DOI: 10.1177/0885066608327127] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
There is a rapidly growing population of immunocompromised organ transplant recipients. These patients are at risk of a large variety of infections that have significant consequences on mortality, graft dysfunction, and graft loss. The diagnosis and treatment of these infections are facilitated by an understanding of the preoperative, perioperative, and postoperative risk factors; the typical pathogens; and their characteristic time of presentation. On the basis of these factors, we put forth an algorithm for diagnosing and treating suspected infections in solid organ transplant recipients.
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Affiliation(s)
- Nicole Hlava
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
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Ogata M, Kadota JI. Human herpesvirus-6 infections and infection-preventative measures in transplant recipients. Future Virol 2008. [DOI: 10.2217/17460794.3.6.567] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Like the other herpesviruses, human herpesvirus (HHV)-6 is capable of persisting in the host after primary infection and can reactivate under immunosuppressed conditions. In stem cell transplantation recipients, HHV-6 reactivation is observed in 40–50% of patients and is linked to various clinical manifestations, including rash, delayed platelet engraftment and encephalopathy. HHV-6 reactivation is also relatively common in solid organ transplantation recipients, and is associated with graft dysfunction and subsequent development of human cytomegalovirus disease. In particular, HHV-6 has been recognized as a life-threatening pathogen for the development of encephalopathy after stem cell transplantation. Ganciclovir, foscarnet and cidofovir are effective against HHV-6 in vitro. However, success rates are not high for patients who have developed encephalopathy. Plasma HHV-6 DNA-guided pre-emptive approaches have not been successful owing to the dynamic kinetics of HHV-6 reactivation. Establishment of optimal strategies is needed to prevent HHV-6-associated complications, in particular encephalopathy.
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Affiliation(s)
- Masao Ogata
- Blood Transfusion Center, Oita University, Faculty of Medicine, Yufu-city, Oita 879-5593, Japan
| | - Jun-ichi Kadota
- Division of Pathogenesis & Disease Control, Department of Infectious Diseases, Oita University, Faculty of Medicine, Yufu-city, Oita 879-5593, Japan
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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: 118] [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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Ohashi M, Sugata K, Ihira M, Asano Y, Egawa H, Takada Y, Uemoto S, Yoshikawa T. Human herpesvirus 6 infection in adult living related liver transplant recipients. Liver Transpl 2008; 14:100-9. [PMID: 18161770 DOI: 10.1002/lt.21304] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
To analyze human herpesvirus 6 (HHV-6) infection in adult living related liver transplantation, we performed a virological analysis, including viral isolation, serological assay, and real-time polymerase chain reaction, of serially collected blood samples from 67 recipients. In addition, cytokine levels were measured to determine their role in viral reactivation. HHV-6 was isolated from only 4 recipients (6.0%), and viral DNA was detected in 15 (22.4%) of the 67 recipients. A significant increase in HHV-6 immunoglobulin G antibody titers was observed in 19 (28.4%) of the 67 recipients. Finally, 26 recipients (38.8%) had HHV-6 reactivation 2-6 weeks after transplantation. HHV-6 associated clinical features were analyzed in the 17 recipients presenting with either viremia or DNAemia. Two recipients with viremia and 3 recipients with DNAemia had unexplained fever at the time of viral infection. An increase in aminotransferase levels was observed in 2 recipients with viremia and 3 recipients with DNAemia. Recipients with liver cirrhosis caused by hepatitis B virus or hepatitis C virus infection as the underlying disease were more likely to have HHV-6 infection (P = 0.025). Mortality at the last follow-up in recipients with HHV-6 reactivation was significantly higher than in those without viral reactivation (P = 0.0118). Plasma interleukin-6 levels were significantly higher in the recipients with HHV-6 viremia than in the recipients without viremia at 4 weeks post-transplant (P = 0.0411). Moreover, tumor necrosis factor alpha levels were also higher in recipients with HHV-6 viremia (P < 0.0001) or reactivation (P = 0.0011) than in recipients without viremia or reactivation 4 weeks post-transplant.
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Affiliation(s)
- Masahiro Ohashi
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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Humar A, Washburn K, Freeman R, Paya CV, Mouas H, Alecock E, Razonable RR. An assessment of interactions between hepatitis C virus and herpesvirus reactivation in liver transplant recipients using molecular surveillance. Liver Transpl 2007; 13:1422-7. [PMID: 17902128 DOI: 10.1002/lt.21266] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatitis C virus (HCV) has been proposed to have immunomodulatory effects in transplant recipients and may promote herpesvirus reactivation. To assess this, we compared the incidence of herpesvirus reactivation in HCV-positive and HCV-negative liver transplant recipients. Quantitative viral load testing was performed at regular intervals posttransplantation for cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesviruses (HHV) 6, 7, and 8, and varicella zoster virus (VZV) in 177 liver transplant patients who were HCV-positive (n=60) or HCV-negative (n=117). The incidence of CMV disease, CMV viremia, and the peak CMV viral load was not significantly different in HCV-positive vs. HCV-negative patients. Similarly, no differences in HHV-6 or EBV reactivation were observed. HHV-8 or VZV viremia was not detected in any patient in the study. A lower incidence of HHV-7 infection occurred in HCV-positive patients vs. HCV-negative patients (47.6% vs. 72.7%; P=0.006). In conclusion, these results suggest that HCV infection does not appear to promote herpesvirus reactivation after liver transplantation.
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Affiliation(s)
- Atul Humar
- Department of Medicine, University of Alberta, Edmonton, AB, Canada.
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31
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Transmission of viral disease to the recipient through the donor liver. Curr Opin Organ Transplant 2007; 12:231-241. [DOI: 10.1097/mot.0b013e32814e6b67] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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32
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Watt KDS, Burak K, Deschênes M, Lilly L, Marleau D, Marotta P, Mason A, Peltekian KM, Renner EL, Yoshida EM. Recurrent hepatitis C post-transplantation: where are we now and where do we go from here? A report from the Canadian transplant hepatology workshop. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 20:725-34. [PMID: 17111055 PMCID: PMC2660828 DOI: 10.1155/2006/238218] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Approximately 400 liver transplants are performed in Canada every year and close to 6000 per year in the United States. Forty per cent to 45% of all liver transplants are performed for patients with underlying hepatitis C virus (HCV)-related liver disease. These patients have a different natural history, new complication risks and different treatment efficacy than nontransplant HCV patients. Every effort must be made to identify those patients at highest risk for progressive liver disease post-transplant. Recurrent HCV is an Achilles' heel to transplant hepatology. The true natural history of this disease is only starting to unravel and many questions remain unanswered on the optimal management of these patients after liver transplantation. The present report summarizes the literature and ongoing research needs that are specific to HCV-related liver transplantation.
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Khettry U, Huang WY, Simpson MA, Pomfret EA, Pomposelli JJ, Lewis WD, Jenkins RL, Gordon FD. Patterns of recurrent hepatitis C after liver transplantation in a recent cohort of patients. Hum Pathol 2006; 38:443-52. [PMID: 17188331 DOI: 10.1016/j.humpath.2006.08.028] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Revised: 08/23/2006] [Accepted: 08/25/2006] [Indexed: 01/08/2023]
Abstract
Clinicopathologic trends of recurrent hepatitis C after liver transplantation (LT) in hepatitis C (HCV) patients seem to have changed in recent years. Our aims were to define the current post-LT patterns of HCV recurrence and identify features of diagnostic and/or prognostic significance. Detailed analysis was performed on 92 HCV patients who underwent LT from June 1999 to December 2003 and survived early post-LT period. The study patients were grouped, as follows: no histologic recurrence (n = 31), "typical" recurrent HCV (n = 52), and post-LT autoimmune-like hepatitis ("AIH-like") (n = 9). The typical and AIH-like groups had mostly common features with post-LT progressive fibrosis (stage > or =2) more frequent in the latter. Based on post-LT progressive fibrosis (stage > or =2), the 2 post-LT hepatitis categories were regrouped as progressive (n = 24) and nonprogressive (n = 37). High viral counts, HCV genotype 1, and native liver inflammation grade 2 or higher with plasmacytic periseptitis were more frequent in progressive cases than nonprogressive or nonrecurrent cases. Sex mismatch of male recipient and female donor was more common in nonrecurrent group. Overall, death rate was comparable in all groups; however, post-LT HCV-related deaths were more common in progressive cases. In conclusion (1) two thirds (66.2%) of HCV patients developed histologic hepatitis after LT with either typical or AIH-like features; (2) progressive fibrosis was seen in 39.3% of patients with post-LT hepatitis and 26% of the entire study group and was more frequent in AIH-like cases; (3) inflammation grade 2 or higher with plasmacytic periseptitis in native livers may be a predictor of post-LT progressive fibrosis; and (4) male recipient/female donor combination was more common in nonrecurrent cases.
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Affiliation(s)
- Urmila Khettry
- Department of Anatomic Pathology, Lahey Clinic Medical Center, Burlington, MA 01805, USA.
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34
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Ljungman P, Singh N. Human herpesvirus-6 infection in solid organ and stem cell transplant recipients. J Clin Virol 2006; 37 Suppl 1:S87-91. [PMID: 17276376 DOI: 10.1016/s1386-6532(06)70018-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
HHV-6 has in recent years become recognized as a potential significant pathogen in both solid organ and stem cell transplant recipients. HHV-6 infections are common after transplantation regardless of the utilized diagnostic technique. Several different clinical manifestations have been described including fever, bone marrow suppression, encephalitis, skin rash, and hepatitis. The most important end-organ disease is encephalitis in stem cell transplant recipients that has been reported to have a mortality of at least 40%. HHV-6 is also considered an immunomodulatory and immunosuppressive virus that may facilitate super-infections with other opportunistic pathogens such as CMV and fungal infections and thereby contribute to overall mortality. No established therapy exists but both ganciclovir and foscarnet have been reported to have in vitro and in vivo efficacy against HHV-6.
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Affiliation(s)
- Per Ljungman
- Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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35
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Griffiths PD. Antivirals in the transplant setting. Antiviral Res 2006; 71:192-200. [PMID: 16793148 DOI: 10.1016/j.antiviral.2006.04.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2006] [Revised: 04/27/2006] [Accepted: 04/28/2006] [Indexed: 12/12/2022]
Abstract
Over the past quarter of a century, antiviral drugs have moved from an experimental adventure in transplant patients to a situation where they are used routinely to prevent diseases caused by several viruses. Furthermore, they have significantly reduced several medical complications of transplantation, such as graft rejection, thereby implicating viruses as components of their pathogenesis. By controlling these major complication, the development of these antiviral drugs and their prodrugs, has therefore greatly facilitated the clinical expansion of transplantation, allowing life saving procedures to be offered to more patients who could potentially benefit. This article will briefly summaries which viruses are important following transplantation and outline the evidence-base from randomized controlled clinical trails for the deployment of antiviral drugs to prevent viral diseases.
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Affiliation(s)
- Paul D Griffiths
- Centre for Virology, Department of Infection, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom.
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Abstract
Antecedent or current infections can alter the immunopathologic outcome of a subsequent unrelated infection. Immunomodulation by co-infecting pathogens has been referred to as 'heterologous immunity' and has been postulated to play a role in host susceptibility to disease, tolerance to organ transplant, and autoimmune disease. The effect of various infections on heterologous immune responses has been well studied in the context of shared epitopes and cross-reactive T cells. It has been shown that prior infections can modulate protective immunity and immunopathology by forming a pool of memory T cells that can cross-react with antigens from heterologous organisms or through the generation of a network of regulatory cells and cytokines. While it is not feasible to alter a host's history of prior infection, understanding heterologous immune responses in the context of simultaneous unrelated infections could have important therapeutic implications. Here, we outline key evidence from animal and human studies demonstrating the effect of heterologous immunity on the outcome of disease. We briefly review the role of T cells, but expand our discussion to explore other immune mechanisms that may modulate the response to concurrent active infections. In particular, we underscore the role of the innate immune system, polarized responses and regulatory mechanisms on heterologous immune responses.
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Affiliation(s)
- Kathleen R Page
- Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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37
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Singh N. Interactions between viruses in transplant recipients. Clin Infect Dis 2005; 40:430-6. [PMID: 15668868 DOI: 10.1086/427214] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2004] [Accepted: 09/24/2004] [Indexed: 01/31/2023] Open
Abstract
Viral coinfections may modulate disease expression, enhance pathogenicity, and lead to greater cumulative immunosuppression in the host. The pathophysiological basis of these may be direct virus-virus interactions, effect of cohabitating viruses on host cell function, or impaired host immune responses. The interrelationship between viral pathogens has become increasingly more relevant and its scope wider as new or previously unrecognized viruses continue to emerge as pathogens in transplant recipients. The pathways and mediators that modulate biological activity represent potential targets for immunomodulatory interventions as adjunctive therapies for transplant recipients.
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Affiliation(s)
- Nina Singh
- Veterans Affairs Medical Center and University of Pittsburgh, Pittsburgh, PA 15240, USA. nis5+@pitt.edu
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De Bolle L, Naesens L, De Clercq E. Update on human herpesvirus 6 biology, clinical features, and therapy. Clin Microbiol Rev 2005; 18:217-45. [PMID: 15653828 PMCID: PMC544175 DOI: 10.1128/cmr.18.1.217-245.2005] [Citation(s) in RCA: 364] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Human herpesvirus 6 (HHV-6) is a betaherpesvirus that is closely related to human cytomegalovirus. It was discovered in 1986, and HHV-6 literature has expanded considerably in the past 10 years. We here present an up-to-date and complete overview of the recent developments concerning HHV-6 biological features, clinical associations, and therapeutic approaches. HHV-6 gene expression regulation and gene products have been systematically characterized, and the multiple interactions between HHV-6 and the host immune system have been explored. Moreover, the discovery of the cellular receptor for HHV-6, CD46, has shed a new light on HHV-6 cell tropism. Furthermore, the in vitro interactions between HHV-6 and other viruses, particularly human immunodeficiency virus, and their relevance for the in vivo situation are discussed, as well as the transactivating capacities of several HHV-6 proteins. The insight into the clinical spectrum of HHV-6 is still evolving and, apart from being recognized as a major pathogen in transplant recipients (as exemplified by the rising number of prospective clinical studies), its role in central nervous system disease has become increasingly apparent. Finally, we present an overview of therapeutic options for HHV-6 therapy (including modes of action and resistance mechanisms).
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Affiliation(s)
- Leen De Bolle
- Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium
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40
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Abstract
Human herpesvirus 6 (HHV-6) exists as distinct variants HHV-6A and HHV-6B. The complete genomes of HHV-6A and HHV-6B have been sequenced. HHV-6B contains 97 unique genes. CD46 is the cell receptor for HHV-6, explaining its broad tissue tropism but its restricted host-species range. HHV-6 utilizes a number of strategies to down-regulate the host immune response, including molecular mimicry by production of a functional chemokine and chemokine receptors. Immunosuppression is enhanced by depletion of CD4 T lymphocytes via direct infection of intra-thymic progenitors and by apoptosis induction. Infection is widespread in infants between 6 months and 2 years of age. A minority of infants develop roseola infantum, but undifferentiated febrile illness is more common. Reactivation from latency occurs in immunocompromised hosts. Organ-specific clinical syndromes occasionally result, but indirect effects including interactions with other viruses such as human immunodeficiency virus type 1 and human cytomegalovirus or graft dysfunction in transplant recipients may be more significant complications in this population. Recent advances in quantitative PCR are providing additional insights into the natural history of infection in paediatric populations and immunocompromised hosts.
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Affiliation(s)
- D H Dockrell
- Division of Genomic Medicine, University of Sheffield School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, UK
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41
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Benito N, Moreno A, Pumarola T, Marcos MA. Virus del herpes humano tipo 6 y tipo 7 en receptores de trasplantes. Enferm Infecc Microbiol Clin 2003; 21:424-32. [PMID: 14525708 DOI: 10.1016/s0213-005x(03)72980-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Recent years have witnessed a growing interest in the role of human herpesvirus (HHV) type 6 and type 7 as emerging pathogens or copathogens in transplant recipients. Both HHV-6 and HHV-7 belong to the beta-herpesvirus family and are closely related to another member of the family, cytomegalovirus. After the primary infection, these viruses remain latent in the human host and can reactivate after transplantation. Various clinical processes such as fever, rash, pneumonitis, encephalitis, hepatitis, and myelosuppression have been described in association with herpesvirus. Moreover, a growing body of evidence suggests that the major impact of HHV-6 and HHV-7 reactivation in transplantation is related to indirect effects, such as their association with cytomegalovirus disease, increased opportunistic infections, and graft dysfunction and rejection. The pathogenesis of HHV-6 and HHV-7 during the post-transplantation period, the methods used for their diagnosis, and the evaluation of antiviral drugs and strategies for their prevention and treatment are now the subject of extensive research.
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Affiliation(s)
- Natividad Benito
- Servicio de Infecciones. Institut Clínic d'Infeccions i Inmunologia. Hospital Clínic Universitari-IDIBAPS. Barcelona. España.
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