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Encephalitis caused by human herpesvirus-6B in pancreas-after-kidney transplantation
Abstract
Human herpesvirus-6 (HHV-6) is a common pathogen among children, classically presenting with fever and rash that resolves without specific therapy. HHV-6 can be reactivated in the immunosuppressed patient. After bone marrow and solid organ transplantation, HHV-6 has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, myelitis, hepatitis, pneumonitis, and bone marrow suppression. However, HHV-6 encephalitis after pancreatic transplant has rarely been reported. Early diagnosis and treatment of HHV-6 encephalitis may be important for affected patients. We report the case of a 53-year-old pancreas-after-kidney transplant recipient who initially presented with high fever and confusion 3 weeks after operation. We managed to save the patient's life and preserve the pancreas graft function. We also review previously reported cases of HHV-6B encephalitis in solid organ transplant recipients.
... In fact, there are only few reports on symptomatic or even fatal cases of HHV-6 disease in kidney transplant recipients. 1,3,6 The spectrum of clinical manifestations is wide, with most severe cases characterized by hemophagocytic syndrome, pancytopenia, encephalitis, severe hepatitis, or colitis. 1,4 Colitis has been previously described as a manifestation of HHV-6 infection; however, in our patient, the intestinal involvement expressed itself in a unique clinical feature, that is, as pseudoobstruction syndrome, characterized by massive gastric, small bowel, and colonic dilatation. ...
... Only a few cases of HHV-6-associated encephalitis after solid-organ transplant have been reported in literature, whereas it has been frequently reported as a fatal disease after hematopoietic stem cell transplant. 6 Clinical symptoms experienced by our patient are similar to those previously described and include confusion, involuntary movements, visual hallucinations, fever, and seizure. 6 When HHV-6 encephalitis is suspected, brain MRI imaging is recommended. ...
... 6 Clinical symptoms experienced by our patient are similar to those previously described and include confusion, involuntary movements, visual hallucinations, fever, and seizure. 6 When HHV-6 encephalitis is suspected, brain MRI imaging is recommended. However, as focal findings may not present in the initial phase of encephalitis, quantitative PCR methods are indicated in order to establish early diagnosis and to initiate antiviral therapy promptly. ...
Human herpesvirus 6 infection is common after organ transplant. Generally, infection is asymptomatic or is associated with a mild illness. However, human herpesvirus 6 infection in these patients may as well be life threatening as a result of severe end-stage organ disease. Here, we have reported a case of a severe human herpesvirus 6 infection with cerebral, hepatic, and gastrointestinal involvement, which presented as intestinal pseudo-obstruction. The patient was a renal transplant recipient who was successfully treated with ganciclovir. We also reviewed the literature on human herpesvirus 6 diagnosis and the associated colitis and encephalitis with its infection in solid-organ transplant recipients.
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.
Herpesviruses are members of a diverse family of viruses that colonize all vertebrates from fish to mammals. Although more than one hundred herpesviruses exist, all are nearly identical architecturally, with a genome consisting of a linear double-stranded DNA molecule (100 to 225 kbp) protected by an icosahedral capsid made up of 162 hollow-centered capsomeres, a tegument surrounding the nucleocapsid, and a viral envelope derived from host membranes. Upon infection, the linear viral DNA is delivered to the nucleus, where it circularizes to form the viral episome. Depending on several factors, the viral cycle can proceed either to a productive infection or to a state of latency. In either case, the viral genetic information is maintained as extrachromosomal circular DNA. Interestingly, however, certain oncogenic herpesviruses such as Marek's disease virus and Epstein-Barr virus can be found integrated at low frequencies in the host's chromosomes. These findings have mostly been viewed as anecdotal and considered exceptions rather than properties of herpesviruses. In recent years, the consistent and rather frequent detection (in approximately 1% of the human population) of human herpesvirus 6 (HHV-6) viral DNA integrated into human chromosomes has spurred renewed interest in our understanding of how these viruses infect, replicate, and propagate themselves. In this review, we provide a historical perspective on chromosomal integration by herpesviruses and present the current state of knowledge on integration by HHV-6 with the possible clinical implications associated with viral integration.
Human herpes virus 6 (HHV6) is known to reactivate after hematopoietic stem cell transplantation (HSCT), and has been suggested to be associated with severe clinical manifestations in adults. The clinical significance in children remains unclear. Weinvestigated the incidence of HHV6 reactivation in relation to HSCT-associated morbidity and mortality in children. Between January 2004 and May 2006, 58 pediatric patients, median age 7.6 years (range: 0.1-18.1 years), received their first allogeneic HSCT. After HSCT, HHV6, Epstein Barr Virus (EBV), cytomegalovirus (CMV), and adenovirus (AdV)-plasma loads were weekly measured by quantitative PCR. Clinical features, engraftment, graft-versus-host disease (GVHD), and HSCT-associated mortality and morbidity were monitored. HHV6 reactivations were classified in group I (no reactivation), group II (loads <1000 cp/ mL) and group III (loads >1000 cp/mL). CMV, EBV, Herpes Simpex Virus, Varicella Zoster Virus, and AdVreactivations were treated according to local guidelines. HHV6 was treated only when there was clinical suspicion of disease. Thirty-six HLA-identical and 22 HLA nonidentical grafts were transplanted of which 43 were bone marrow or peripheral blood stem cells grafts and 15 were cord blood (CB) grafts. Median follow-up of the patients was 15.5 (1-35) months. HHV6 reactivation occurred in 39 of 58 (67%) patients with 31 of 39 (80%) occurring within the first 30 days post-HSCT. In 26 of 58 (45%) patients (group III), HHV 6 reactivation was significantly associated with higher nonrelapse mortality (P5.02), using multivariate Cox proportional hazard models and grade 2-4 acute GVHD (P=.03) and chronic GVHD (P=.05) in a multivariate logistic regression analysis. HHV6 reactivation is very common after HSCT in children and is associated with serious transplantation-related morbidity and mortality. Although the exact role of HHV6 reactivation after HSCT has to be elucidated, early detection and initiation of therapy might be of benefit.
After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC(50) of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC(50) in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an A-->G substitution of the U69 protein kinase (PK) gene resulted in an M(318)V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A(961)V amino acid substitution within the DNA polymerase. The M(318)V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M(460)V and M(460)I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M(318)V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the M(318)V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.
Human herpesvirus-6 (HHV-6), a beta herpesvirus closely related to cytomegalovirus (CMV), infects the majority of the population in childhood. Human herpesvirus-6 can be reactivated in the immunosuppressed patient. After bone marrow and orthotopic liver transplant, it has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, pneumonitis and bone marrow suppression. To date its infectious role after orthotopic heart transplant has not been well documented. We present the case of a 32-year-old cardiac transplant recipient who initially presented 8 weeks after his transplant with high fever and headache. He developed increasing confusion, pulmonary infiltrates and neutropenia. Cytomegalovirus viral loads were negative. Polymerase chain reaction (PCR) of blood and cerebrospinal fluid detected HHV-6 DNA, consistent with HHV-6-related encephalitis, pneumonitis and bone marrow suppression. He was treated with foscarnet with gradual improvement in clinical status. We review the literature on the significance of this virus post cardiac transplant.
We describe the first known case of symptomatic infection resulting from human herpesvirus-6 (HHV-6) in simultaneous pancreas-kidney transplant recipients. The role of HHV-6 in solid-organ transplant recipients is not well defined. In hematopoietic stem cell transplantation (SCT) HHV-6 may cause fever, rash, myelosuppression, interstitial pneumonitis, and encephalitis.
BACKGROUND: Human herpesvirus-6 (HHV-6) is known to reactivate after renal transplantation and has been associated with several clinical manifestations. Risk factors for sustained viral replication, however, remain unclear. METHODS: Thirty consecutive kidney transplant patients were prospectively followed for HHV-6 replication between February 2007 and February 2008. Plasma samples for DNA detection were collected from the donor and the recipient before transplantation and from the recipient weekly for the first 2 months after transplantation and then every 2 weeks for 2 additional months. HHV-6 active infection was defined as detection of viral DNA in plasma, by polymerase chain reaction, in at least two consecutive samples over an interval of at least 1 week. RESULTS: Active viral infection was detected in 25% of the recipients before transplantation and 27% (8 of 30) of the patients after transplantation. The mean time to onset of viral replication was 28.1 days after transplantation and 7 of 8 (87.5%) were asymptomatic. Risk factors associated with active HHV-6 infection were receiving an organ from a living donor (P=0.028), recipients with IgM antibodies detected before transplantation (P=0.005), and pretransplantation recipient HHV-6 viral load more than 10,000 copies/mL plasma (P=0.034). CONCLUSIONS: Active HHV-6 infection occurs early after renal transplantation and is mostly asymptomatic. Donor or recipient infection may occur at the time of transplantation and are related to higher rates of posttransplantation infections.
Report cards evaluating transplant center performance have received significant attention in recent years corresponding with the Centers for Medicare and Medicaid Services issue of the 2007 Conditions of Participation. Our primary aim was to evaluate the association of report card evaluations with transplant center volume. We utilized data from the Scientific Registry of Transplant Recipients (SRTR) along with six consecutive program-specific reports from January 2007 to July 2009 for adult kidney transplant centers. Among 203 centers, 46 (23%) were low performing (LP) with statistically significantly lower than expected 1-year graft or patient survival at least once during the study period. Among LP centers, there was a mean decline in transplant volume of 22.4 cases compared to a mean increase of 7.8 transplants among other centers (p = 0.001). Changes in volume between LP and other centers were significant for living, standard and expanded criteria deceased donor (ECD) transplants. LPs had a reduction in use of donors with extended cold ischemia time (p = 0.04) and private pay recipients (p = 0.03). Centers without low performance evaluations were more likely to increase the proportion of overall transplants that were ECDs relative to other centers (p = 0.04). Findings indicate a significant association between reduced kidney transplant volume and low performance report card evaluations.
Human herpesvirus-6 (HHV-6) is unique among human herpesviruses because of its ability to integrate into chromosomes. This entity, termed chromosomally integrated HHV-6 (CIHHV-6), is often mistaken for active infection and treated unnecessarily. The clinical significance of CIHHV-6 in transplant recipients is not defined. Herein, the clinical characteristics of 7 liver transplant patients with CIHHV-6 from our recent study, together with 14 other published cases of CIHHV-6 were reviewed. Of the 21 cases, CIHHV-6B was reported most commonly among solid organ transplant recipients, while CIHHV-6A was mostly seen in allogeneic hematopoietic stem cell recipients. None of the 21 patients developed clinical symptoms related to HHV-6 after transplantation. However, antiviral therapy was administered to 5 asymptomatic patients mistaken to have HHV-6 infection because of their very high HHV-6 DNA levels, 3 who developed symptomatic cytomegalovirus disease, and 1 with graft-versus-host disease that was mistaken for HHV-6 infection. In patients who received antiviral therapy, there was no apparent decline in HHV-6 DNA load, although change in viral kinetics is difficult to discern in the setting of high baseline HHV-6 DNA load. Clinicians should be aware of this entity of CIHHV-6 so that antiviral therapy can be considered in the proper clinical context.
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.
It is important to differentiate human herpesvirus 6 (HHV-6)-associated encephalopathy from herpes simplex encephalitis (HSE). Although these conditions are similar with regard to involvement of the mesial temporal lobe, HSE is sensitive to acyclovir but HHV-6 encephalopathy is not. We compared the imaging findings of the two conditions.
We encountered eight cases of HHV-6 encephalopathy and nine cases of HSE. We divided an observation time into early, middle, and late periods defined as 0-2, 3-30, and more than 30 days from the onset of neurologic symptoms. Differences between HHV-6 encephalopathy and HSE on CT scans in the early period and in distribution and temporal changes in the affected regions on MR images in the three periods were analyzed.
At MRI in the early and middle periods, all eight patients with HHV-6 encephalopathy had exclusive involvement of the mesial temporal lobes, and all nine patients with HSE had involvement of both the mesial temporal lobes and the extratemporal regions (p < 0.01). Among patients who underwent head MRI, six of six with HHV-6 encephalopathy but none of six with HSE had resolution of high signal intensity on T2-weighted and FLAIR images (p < 0.01). Among patients who underwent head CT in the early period, none of the four with HHV-6 encephalopathy and six of the seven with HSE had abnormal findings, including parenchymal swelling, decreased attenuation of affected regions, and abnormal gyral enhancement (p < 0.05).
Serial MRI showed transient abnormal signal intensity in the mesial temporal lobes in patients with HHV-6 encephalopathy but persistent abnormal signal intensity in both the mesial temporal lobes and the extratemporal regions in patients with HSE. CT in the early period showed no abnormality in patients with HHV-6 encephalopathy but definite abnormal findings in patients with HSE. These differences may be useful in the differential diagnosis of the two conditions.
Human herpesvirus 6 (HHV-6) is a common pathogen among children, classically presenting as fever and rash that resolve without specific therapy (exanthem subitum or roseola infantum). Also identified as a pathogen in hematopoietic cell transplant and solid organ transplant (SOT) recipients, it has been recognized as a cause of limbic encephalitis, characterized by confusion and amnesia, with magnetic resonance imaging findings of T2 hyperintensity of the amygdala and hippocampus. We report a case of limbic encephalitis associated with HHV-6 infection in a liver transplant recipient, and we review previously reported cases of HHV-6 encephalitis in SOT recipients.
Recent reports have documented human herpesvirus 6 (HHV-6) as a cause of high fever, bone marrow depression, and rash in liver transplant recipients in the absence of another known pathogen. We describe a 49-year-old liver transplant recipient who developed confusion, occipital headache, and involuntary movements of the limbs 3 weeks after orthotopic liver transplantation. HHV-6 was detected in the peripheral blood using a rapid culture assay. Examination of cerebrospinal fluid by polymerase chain reaction for HHV-6 was also positive. No other pathogens were identified. The patient improved after commencement of intravenous ganciclovir therapy. This case suggests HHV-6 needs to be considered in the differential diagnosis of unexplained confusion in liver transplant recipients.
The beta-herpesvirus human herpesvirus-6 (HHV-6) is becoming increasingly recognized as an important pathogen in immunocompromised patients, particularly in post bone marrow transplant (BMT). Reactivation of latent HHV-6 resulting in encephalitis has been reported in BMT and stem cell transplant (SCT) patients. The development of HHV-6 encephalitis can be a fatal complication, the frequency of which is increasing likely due to improved diagnosis with quantitative polymerase chain reaction (PCR) of cerebrospinal fluid. There are currently no antiviral compounds approved for HHV-6, nor have any controlled clinical trials been conducted. The frequency and severity of HHV-6 encephalitis in both immunocompetent and immunocompromised patients necessitates studies on the usefulness of currently available anti-viral compounds. The authors compared the antiviral efficacy of four drugs currently used for cytomegalovirus (CMV) infection, a beta-herpesvirus sharing homology with HHV-6. In HHV-6A- and HHV-6B-infected T cells, acyclovir, ganciclovir, foscarnet, and cidofovir exhibited antiviral activity consistent with that published in other studies. In HHV-6-infected human astrocytes (U251), however, only foscarnet and cidofovir exhibited antiviral activity and this effect was restricted to infection with HHV-6 variant A. In pathological brain sections from patients with neurological disorders such as multiple sclerosis and epilepsy, HHV-6 has been localized to glial cells. Determination of antiviral activity in human glial fibrillary acidic protein (GFAP)-positive astrocytes of currently used antiviral compounds is essential for potential treatment of HHV-6 and neurological disorders. Our data highlight the necessity for further study of antiviral compound in HHV-6-infected glial cells as well as the development of more selective compounds for HHV-6.
Human herpesvirus 6 infects virtually all children within the first few years of life and like other herpesviruses, establishes latency after primary infection. In immunocompromised hosts, especially hematopoietic cell transplant (HCT) recipients, HHV-6 has been demonstrated to reactivate frequently. This reactivation has been associated with a number of different clinical endpoints in HCT recipients, including central nervous system (CNS) disease. There have been many detailed descriptions of individual patients with HHV-6-associated encephalitis. In addition, longitudinal observational studies have established a correlation between systemic HHV-6 reactivation and CNS dysfunction. Further research is needed to define optimal diagnostic, prevention, and treatment strategies.
Acute limbic encephalitis has been reported in the setting of treatment-related immunosuppression and attributed to human herpesvirus-6 (HHV6) infection. Clinical and laboratory features of the syndrome, however, have not been well characterized.
We describe the clinical, EEG, MRI, and laboratory features of nine patients with acute limbic encephalitis after allogeneic hematopoietic stem cell transplantation (HSCT). To explore the relationship between HHV6 and this syndrome, we reviewed available CSF HHV6 PCR results from all HSCT patients seen at our center from March 17, 2003, through March 31, 2005.
Patients displayed a consistent and distinctive clinical syndrome featuring anterograde amnesia, the syndrome of inappropriate antidiuretic hormone secretion, mild CSF pleocytosis, and temporal EEG abnormalities, often reflecting clinical or subclinical seizures. MRI showed hyperintensities within the uncus, amygdala, entorhinal area, and hippocampus on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences. CSF PCR assays for HHV6 were positive in six of nine patients on initial lumbar puncture. All patients were treated with foscarnet or ganciclovir. Cognitive recovery varied among long-term survivors. The one brain autopsy showed limbic gliosis and profound neuronal loss in amygdala and hippocampus. Among 27 HSCT patients with CSF tested for HHV6 over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis.
Patients undergoing allogeneic hematopoietic stem cell transplantation are at risk for post-transplant acute limbic encephalitis (PALE), a distinct neurologic syndrome. Treatment considerations should include aggressive seizure control and, possibly, antiviral therapy. PALE can be associated with the CSF presence of human herpesvirus-6, but the pathogenic role of the virus requires further exploration.
AST Infectious Diseases Community of Practice. HHV-6, HHV-7 and HHV-8 in solid organ transplant recipients
- R R Razonable
- D M Zerr
Razonable RR, Zerr DM; AST Infectious Diseases Community of
Practice. HHV-6, HHV-7 and HHV-8 in solid organ transplant
recipients. Am J Transplant 2009; 9: S97-S100.
Monitoring for HHV-6 infection after renal transplantation: evaluation of risk factors for sustained viral replication
- C R Luiz
- C M Machado
- C L Canto
Luiz CR, Machado CM, Canto CL, et al. Monitoring for HHV-6
infection after renal transplantation: evaluation of risk factors for
sustained viral replication. Transplantation 2013; 95: 842-846.
Monitoring for HHV-6 infection after renal transplantation: evaluation of risk factors for sustained viral replication
- Luiz