Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review

Lautenschlager, Irmeli; Razonable, Raymund R.

doi:10.1111/j.1432-2277.2012.01443.x

Cited by 94 publications

(84 citation statements)

References 104 publications

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“…25 In addition to encephalitis, HHV-6 reactivation has been associated with an increased risk of GVHD, delayed engraftment, cytopenia, opportunistic infections and fever. 19,[26][27][28][29][30][31] There is still a considerable uncertainty on the clinical significance of HHV-6 reactivation, and routine testing for HHV-6 is not currently performed at most transplant centers. The purpose of our study was to conduct a systematic review of the literature and a meta-analysis to clarify the relationship between CBT and HHV-6 reactivation and assess the pooled prevalence of encephalitis among CBT patients.…”

Section: Introductionmentioning

confidence: 99%

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

Scheurer

Pritchett

Amirian

et al. 2012

Bone Marrow Transplant

108

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Reactivation of human herpesvirus-6 (HHV-6) frequently occurs following hematopoietic SCT (HSCT), and has been associated with clinical consequences in many patient populations. HHV-6 reactivation and HHV-6 encephalitis seem to occur more frequently in patients undergoing HSCT with cord blood (CB) as the stem cell source. We have conducted a systematic literature review and meta-analysis to investigate the clinical significance of this correlation. A systematic review of publications indexed in PubMed was performed for HSCT studies published over the past 10 years that fit inclusion criteria. Data on prevalences of HHV-6 reactivation and HHV-6 encephalitis post HSCT were abstracted from 19 papers. Meta-analyses were conducted to calculate combined prevalence estimates. The prevalences of HHV-6 reactivation and encephalitis were compared among CB vs non-CB HSCT. Prevalences of HHV-6 reactivation and HHV-6 encephalitis were significantly higher in patients receiving CB as the stem cell source than in patients receiving another stem cell source (72.0% vs 37.4%, Po0.0001; 8.3% vs 0.50%, Po0.0001, respectively). HHV-6 reactivation and HHV-6 encephalitis are significant complications in the post-HSCT setting, particularly in patients receiving CB as the stem cell source. Thus, patients undergoing umbilical CB transplantation should be closely monitored for HHV-6 reactivation.

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Section: Introductionmentioning

confidence: 99%

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

Scheurer

Pritchett

Amirian

et al. 2012

Bone Marrow Transplant

108

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“…Viral reactivation can result in delayed transplant engraftment and severe complications up to lethal encephalitis (5). Furthermore, transplantation of solid organs-including kidney, liver, lung, and heart-results in high rates of HHV-6 reactivation, although only 1% of transplant recipients were found to develop severe complications (6). There is no acute disease known to be caused by HHV-6A, but recent studies have suggested potential involvement in multiple sclerosis (MS) aggravation (7).…”

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confidence: 99%

Human herpesvirus 6 (HHV-6) alters E2F1/Rb pathways and utilizes the E2F1 transcription factor to express viral genes

Sharon

Volchek

Frenkel

2013

Proc. Natl. Acad. Sci. U.S.A.

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E2F transcription factors play pivotal roles in controlling the expression of genes involved in cell-cycle progression. Different viruses affect E2F1/retinoblastoma (Rb) interactions by diverse mechanisms releasing E2F1 from its suppressor Rb, enabling viral replication. We show that in T cells infected with human herpesvirus 6A (HHV-6A), the E2F1 protein and its cofactor DP1 increased, whereas the Rb protein underwent massive degradation without hyperphosphorylation at three sites known to control E2F/Rb association. Although E2F1 and DP1 increased without Rb suppression, the E2F1 target genes-including cyclin A, cyclin E, and dihydrofolate reductase-were not up-regulated. To test whether the E2F1/DP1 complexes were used for viral transcription, we scanned the viral genome for genes containing the E2F binding site in their promoters. In the present work, we concentrated on the U27 and U79 genes known to act in viral DNA synthesis. We constructed amplicon-6 vectors containing a GFP reporter gene driven by WT viral promoter or by promoter mutated in the E2F binding site. We found that the expression of the fusion U27 promoter was dependent on the presence of the E2F binding site. Test of the WT U79 promoter yielded >10-fold higher expression of the GFP reporter gene than the mutant U79 promoter with abrogated E2F binding site. Moreover, by using siRNA to E2F1, we found that E2F1 was essential for the activity of the U79 promoter. These findings revealed a unique pathway in HHV-6 replication: The virus causes Rb degradation and uses the increased E2F1 and DP1 factors to transcribe viral genes.H uman herpesvirus 6A (HHV-6A) and HHV-6B infect >90% of children by the age of 2 y (1). Recent studies have found that ∼1% of children are born with chromosomally integrated HHV-6, suggesting that the virus is vertically transmitted in a Mendelian manner (2). HHV-6B is the causative agent of roseola infantum, a brief febrile infection with skin rash (3). In a minority of patients, there are neurological complications up to lethal encephalitis (4). After productive infection, HHV-6B enters into latency from which it can be reactivated-e.g., following bone marrow and hematopoietic stem cell transplantations. Viral reactivation can result in delayed transplant engraftment and severe complications up to lethal encephalitis (5). Furthermore, transplantation of solid organs-including kidney, liver, lung, and heart-results in high rates of HHV-6 reactivation, although only 1% of transplant recipients were found to develop severe complications (6). There is no acute disease known to be caused by HHV-6A, but recent studies have suggested potential involvement in multiple sclerosis (MS) aggravation (7). HHV-6 was found more often in MS plaques than in MS normal-appearing white matter or non-MS brains. HHV-6 reactivation has been reported during MS clinical relapses (7). Recent evidence (8) has suggested the association of HHV-6A with Hashimoto thyroiditis, the most common of all thyroid diseases.E2F1 acts as a transcription factor of ...

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“…125 Symptoms and signs attributed to HHV-6 include fever, rash, cytopenia, interstitial pneumonitis, hepatitis but a definite causeand-effect relationship with HHV-6 is often lacking. 126,127,128 The virus may have immunosuppressive effects through interaction with CMV or by affecting the immune system directly. An association between invasive fungal infections and HHV-6 has been suggested.…”

Section: Herpes Simplex Virus and Varicella Zoster Virusmentioning

confidence: 99%

“…Currently available serologic tests available are of limited value because of high seroprevalence in the general population and also because transplant recipients receiving immunosuppressive medication may not mount a serologic response. 128 Sensitive polymerase chain reaction-based detection of HHV-6 may detect latent virus and overestimate the presence of infection. Antiviral agents active against CMV are also active against HHV-6, including ganciclovir, foscarnet, and cidofovir.…”

Section: Herpes Simplex Virus and Varicella Zoster Virusmentioning

confidence: 99%

Infections After Orthotopic Liver Transplantation

Pedersen

Seetharam

2014

Journal of Clinical and Experimental Hepatology

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Opportunistic infections are a leading cause of morbidity and mortality after orthotopic liver transplantation. Systemic immunosuppression renders the liver recipient susceptible to de novo infection with bacteria, viruses and fungi post-transplantation as well to reactivation of pre-existing, latent disease. Pathogens are also transmissible via the donor organ. The time from transplantation and degree of immunosuppression may guide the differential diagnosis of potential infectious agents. However, typical systemic signs and symptoms of infection are often absent or blunted after transplant and a high index of suspicion is needed. Invasive procedures are often required to procure tissue for culture and guide antimicrobial therapy. Antimicrobial prophylaxis reduces the incidence of opportunistic infections and is routinely employed in the care of patients after liver transplant. In this review, we survey common bacterial, fungal, and viral infections after orthotopic liver transplantation and highlight recent developments in their diagnosis and management. ( J CLIN EXP HEPATOL 2014;4:347-360) I nfection after orthotopic liver transplantation (OLT) is a major cause of morbidity and mortality. Infection is estimated to occur in upto 80% of organ recipients. Bacterial infections are most frequent (70%), followed by viral (20%) and fungal infections (8%). 1,2,3 In addition to direct effects of infection and end-organ inflammation, pathogens may have a number of indirect effects that result in allograft injury, rejection and opportunistic superinfection.The risk of infection in liver transplant recipients is determined by the intensity of exposure to infectious agents and the overall level of immunosuppression. 4 In addition, conditions attendant to end-stage liver disease in the immediate perioperative period may render a recipient vulnerable to infection and include: neutropenia, deficits in mucocutaneous barrier integrity, presence of necrotic tissue, ischemia, diabetes mellitus, immunomodulating viruses, uremia, and protein-calorie malnutrition. 5 Infectious exposures come from many sources post liver transplant including: de novo (acquired acute) in the recipient, reactivation in the recipient, the donor organ, and nosocomial and time from transplant may provide clues to etiology (Figure 1). The overall level of immunosuppression is dependent upon the dose, duration, and choice of immunosuppression as well as underlying immune deficiencies. 6 Inflammatory responses to invading pathogens are often blunted by immunosuppressive therapy, and as a result, the classic signs or symptoms of infection may be absent. A high index of suspicion is need in the liver recipient, and a low threshold to perform invasive diagnostic procedures is often required. It is critical to identify clinical factors that predispose recipients to infection and much interest centers on identifying risk factors for infection after liver transplant. GENETIC POLYMORPHISMS IN THE INNATE IMMUNE SYSTEMIn addition to clinical factors that promote ...

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Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review

Cited by 94 publications

References 104 publications

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

Human herpesvirus 6 (HHV-6) alters E2F1/Rb pathways and utilizes the E2F1 transcription factor to express viral genes

Infections After Orthotopic Liver Transplantation

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