Persistent lack of human herpesvirus-6 specific T-helper cell response in liver transplant recipients.

BACKGROUND: Specific immunologic defects predisposing to human herpesvirus-6 (HHV-6), e.g. the role of HHV-6 specific T-helper cell memory response in liver transplant recipients, have not been assessed. METHODS: T-helper function (mitogen ConA response) as a marker of overall immunocompetence and T-helper response (memory response) specific to HHV-6 and cytomegalovirus (CMV) were assessed in 15 liver transplant recipients and compared with 25 healthy subjects. Samples were tested pretransplant, at 2 weeks, 1 month, 2-3 months, and 1 year posttransplantation. Stimulation index (SI) >3 was considered a positive response. RESULTS: Seven percent (1/15) of the transplant recipients at any time posttransplantation, as compared to 64% (16/25) of the healthy subjects, had a positive HHV-6 memory response (P = 0.00065). HHV-6-specific memory response in transplant recipients at 2 weeks (SI 1.43), 1 month (SI 1.1), and 2-3 months (SI 1.3) was significantly more suppressed than in healthy subjects (SI 17.5, P = 0.0001). Although transplant recipients as compared to healthy subjects also had a lower CMV-specific memory response posttransplant (P = 0.0439), CMV-specific memory response recovered significantly at 1 month (P = 0.03) and at 2-3 months (P = 0.027) as compared to that at 2 weeks. However, HHV-6 memory response was persistently absent up to 2-3 months with partial recovery at 1 year; 7% of the patients at 2-3 months, but 25% at 1 year had a positive HHV-6 specific memory response. Forty percent (6/15) of the patients developed HHV-6 viremia a mean of 4 weeks posttransplant. Patients with HHV-6 viremia had greater suppression of HHV-6 memory response at 1 month than those without viremia (mean SI, 0.96 vs. 1.3, P = 0.08). All but one of the patients had a positive ConA response. CONCLUSION: Prolonged suppression of HHV-6 memory response, but not overall T-helper cell function was documented and may play a role in the pathogenesis of HHV-6 infection in liver transplant recipients. Memory response to CMV after liver transplantation was significantly more robust than to HHV-6.

Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease.

By means of immunohistochemical staining, cells actively infected with human herpesvirus 6 (HHV-6) were found in central nervous system tissues from 8 (73%) of 11 patients with definite multiple sclerosis (MS). Interestingly, 17 (90%) of 19 tissue sections showing active demyelination were positive for HHV-6-infected cells compared with only 3 (13%) of 23 tissue sections free of active disease (P<.0001). Central nervous system tissues from 2 of 28 normal persons and patients with other inflammatory demyelinative diseases were positive for HHV-6-infected cells (P<.0001), and the 2 positive cases were diagnosed as having HHV-6 leukoencephalitis. By use of a rapid culture assay, blood samples from 22 (54%) of 41 patients with definite MS were found to contain active HHV-6 infections, compared with 0 of 61 normal controls (P<.0001). No significant difference was found between HHV-6 viremia-positive and HHV-6 viremia-negative MS patients with respect to type of disease (relapsing/remitting or progressive). In contrast, patients with active HHV-6 viremia were significantly younger and had shorter durations of disease than did HHV-6 viremia-negative patients.

Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome.

BACKGROUND: The clinical impact and relevance of human herpesvirus-6 (HHV-6) infection in liver transplant recipients, has not been fully discerned. METHODS: A prospective study of 80 consecutive liver transplant recipients was performed using surveillance cultures for HHV-6 at weeks 2, 3, 4, and 6 after transplantation. Viral isolation was used for the detection of HHV-6. RESULTS: HHV-6 infection occurred in 39% (31 of 80) of the patients. Patients with HHV-6 infection were more likely to have hepatocellular carcinoma as underlying liver disease (P=.09). Mental status changes of unidentifiable etiology were significantly more likely to occur in patients with HHV-6 compared with those without (26%, 9 of 31 vs. 6%, 3 of 49, P=.008). HHV-6 infection was an independent predictor of invasive fungal infections (odds ratio 8.3, 95% confidence interval, 1.2-58.0, P=.03). A significant association between HHV-6 infection and CMV infection after transplantation, CMV recipient and donor serostatus, rejection, or fever of unknown origin, could not be documented. Mortality at last follow-up in patients with HHV-6 infection (29%, 9 of 31) was significantly greater than those without HHV-6 (6%, 3 of 49, P=.008). CONCLUSIONS: Central nervous system complications of unknown etiology after liver transplantation may be related to HHV-6 infection. HHV-6 viremia was an independently significant predictor of invasive fungal infections and was associated with late mortality in liver transplantation recipients.

Human herpesvirus 6: diagnosis of active infection.

HHV-6 is an opportunistic viral pathogen that has been demonstrated as the cause of often life-threatening illness in pediatric patients and transplant recipients. A substantial body of scientific evidence links HHV-6 to the etiology of such chronic diseases as multiple sclerosis. For these reasons, it is important that patients in these groups be screened for possible infection with HHV-6. Serological studies for IgG and/or IgM can be misleading, as are PCR analyses, which cannot distinguish between latent and actively replicating virus. Currently, the only reliable method for diagnosing an active infection with HHV-6 is viral isolation.

Encephalopathy associated with human herpesvirus 6 in a liver transplant recipient.

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.

Counselor prompts to increase condom taking during treatment for cocaine dependence.

This study examined whether active prompting would increase the number of free condoms taken from dispensers placed in counselors' offices in a cocaine abuse treatment clinic. Using a combined multiple baseline and reversal design, two teams of counselors were instructed to actively prompt and encourage condom taking during some conditions and to avoid commenting on or encouraging condom use in other conditions. To monitor accuracy of implementing the intervention, counselors completed a checklist for every subject they saw in their office during the day. Overall, the number of condoms taken per visit during prompting conditions was almost six times greater than during baseline conditions. However, implementation declined during the study, and all counselors complained about the intervention. Implications for dispensing free condoms to reduce HIV risk in drug abuse treatment clinics are discussed.

PIP: HIV infection is increasing among noninjecting as well as iv drug users. Of particular concern, are users of cocaine and crack cocaine, who are likely to trade sex for money or drugs and to have multiple sexual partners. This study investigated whether an active counselor intervention could increase the number of free condoms taken from dispensers placed in counselors' offices in a cocaine abuse treatment program in Philadelphia, Pennsylvania (US). A multiple baseline design across 2 teams of counselors with reversals was utilized. During the initial 5-week baseline period, when condoms were displayed on the counselors' desks but no prompts were given, an average of 0.34 and 0.25 condoms were taken per visit per team. During weeks 6-13, when counseling Team 1 utilized prompting and encouraged condom taking, this average increased to 3.17/visit. When Team 2 implemented the intervention (weeks 13-20), an average of 2.78 condoms/visit were taken. When both teams stopped the intervention, the number of condoms taken fell close to baseline levels. Resumption of the intervention increased use, but not to the previous high level. Over the entire 28-week study period, clients took an average of 0.43 condoms/visit during baseline conditions, and 2.45/visit during counselor prompting conditions. The 6-fold increase in condom uptake associated with active encouragement suggests the feasibility of this strategy for cocaine treatment programs. However, the participating counselors voiced irritation with the mandatory, sometimes intrusive intervention. The availability of free condoms in the clinic waiting area or day room represents an alternative strategy documented to increase the taking of condoms.

Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity.

BACKGROUND: The new herpesvirus, human herpesvirus-6 (HHV-6), is able to cause clinical illness after transplantation; however, the pathogenic potential and the clinical features of HHV-6 have not been defined in liver transplant recipients. METHODS: We report the first cases of invasive and symptomatic infection due to HHV-6 in liver transplant recipients. RESULTS: HHV-6 infection occurred in four liver transplant recipients at a median of 50 days after transplant (range 17-90 days). Severe cytopenia was observed in all patients; leukopenia (with median leukocyte count of 1400/mm3) was the most commonly effected bone marrow lineage. One of the four patients had interstitial pneumonitis due to HHV-6. No other virus (e.g., cytomegalovirus) or another pathogen was detected in the lungs, blood, or bone marrow in any of the above patients. CONCLUSIONS: Our data suggest that HHV-6 can be a pathogen in liver transplant recipients; idiopathic bone marrow suppression is its predominant clinical sequelae. Recognition of HHV-6 infection is clinically pertinent because HHV-6 is potentially treatable with the currently available antiviral agents.

Adenovirus infections in immunocompromised patients.

Adenovirus infections have been reported in as many as one-fifth of bone marrow transplant (BMT) recipients and patients with acquired immunodeficiency syndrome (AIDS), and in a lesser, though still prominent, proportion of organ transplant recipients. The relative contributions of primary infections versus reactivations from latency in immunocompromised patients remain unclear. Compared with adult BMT recipients, pediatric BMT recipients appear to be infected by adenovirus more frequently and earlier in the post-transplant period. The diagnosis of adenovirus infection is complicated by the existence of > 40 viral serotypes, although certain subgroups are more likely to be involved in certain patient populations. Adenoviruses are responsible for a broad range of clinical diseases that may be associated with high mortality, including pneumonia, hepatitis, encephalitis, hemorrhagic cystitis, and gastroenteritis. The clinical and histopathologic features of adenovirus disease may resemble those of cytomegalovirus disease, potentially complicating the diagnosis. Risk factors for clinical adenovirus disease include the number of sites from which the virus is cultured and, in BMT recipients, the presence of moderate to severe acute graft-versus-host disease.

Prevalence of human herpesvirus 6 in lung tissue from children with pneumonitis.

AIMS/BACKGROUND: Human herpesvirus type 6 (HHV-6) is the aetiological agent of exanthem subitum, and has also been linked with a variety of other diseases. The aim of this study was to investigate the role of HHV-6 in pneumonitis in children. METHODS: Formalin fixed, paraffin wax embedded lung tissue from 33 children (age range two months to 16 years) who died with pneumonitis was subjected to immunohistochemical staining for HHV-6 using an avidin-biotin method. RESULTS: Active HHV-6 infection was demonstrated in four children: a bone marrow transplant recipient with concomitant adenovirus infection, a patient with hepatitis of unknown aetiology, a patient with congenital anomalies, and a patient with congenital immunodeficiency. CONCLUSION: Accurate localisation of HHV-6 is possible in postmortem lung tissue. HHV-6 either alone or in combination with other pathogens may play a role in the development of pneumonitis.

Subacute leukoencephalitis caused by CNS infection with human herpesvirus-6 manifesting as acute multiple sclerosis.

Several recent reports have documented the neuroinvasiveness of human herpesvirus-6 (HHV-6) in infants with primary HHV-6 infections, in children and adults with AIDS, in recipients of bone marrow transplants, and in immunologically intact adults and children. CNS infections with HHV-6 can be subacute and are frequently associated with diffuse or multifocal demyelination. We analyzed the CNS tissues of a young woman who died of a demyelinative disease, which was clinically and histopathologically diagnosed as acute multiple sclerosis, for active HHV-6 infection by immunohistochemical staining. The tissues contained a dense and disseminated active HHV-6 infection that was intimately related to the pathologic changes present.

Human herpesvirus-6 in transplantation: an emerging pathogen.

BACKGROUND: Human herpesvirus-6 can be an opportunistic pathogen in transplant recipients. PURPOSE: To summarize the epidemiologic and clinical aspects of human herpesvirus-6 infection, the immunologic basis of the pathogenicity of human herpesvirus-6, and the management of human herpesvirus-6 infection in transplant recipients. DATA SOURCES: English-language articles identified through a MEDLINE search from 1986 (when human herpesvirus-6 was discovered) to the present, bibliographies of identified articles, and recognized texts. STUDY SELECTION: Reports on human herpesvirus-6 infections in bone marrow transplant recipients and in solid organ transplant recipients. DATA EXTRACTION: Data on the virology, detection, epidemiology, clinical features, and treatment of human herpesvirus-6 infection were manually abstracted from the indicated sources and summarized. Data quality and validity were independently assessed by both authors. DATA SYNTHESIS: Human herpesvirus-6 infection occurred in 38% to 60% of bone marrow transplant recipients and 31% to 55% of solid organ transplant recipients, usually 2 to 4 weeks after transplantation. Human herpesvirus-6 has two variants, designated variant A and variant B; transplant recipients were infected almost exclusively with variant B. Bone marrow suppression, interstitial pneumonitis, and encephalitis were the most commonly reported types of clinical disease caused by human herpesvirus-6. The marrow-suppressive effect of human herpesvirus-6 ranged from transient or self-limited bone marrow suppression to chronic or fatal aplastic anemia; bone marrow suppression was thought to be partially cytokine-mediated. Because it can depress cell-mediated immunity, human herpesvirus-6 may facilitate superinfection by other pathogens. Human herpesvirus-6 resembles cytomegalovirus in its antiviral susceptibilities: It is resistant to acyclovir but susceptible to ganciclovir and foscarnet. Prophylaxis of human herpesvirus-6 infection is feasible in transplant recipients, but this issue must be studied further. CONCLUSION: Human herpesvirus-6 can be a pathogen in transplant recipients. Prompt recognition of disease associated with human herpesvirus-6 is important because this virus is susceptible to currently available antiviral agents. Future research should focus on delineating the complete clinical spectrum, immunologic sequelae, and efficacy of prophylactic strategies for human herpesvirus-6 infection in transplant recipients.

Active HHV-6 infection in the lymph nodes of HIV-infected patients: in vitro evidence that HHV-6 can break HIV latency.

Studies published previously by this laboratory have demonstrated that patients with AIDS have widely disseminated, active infections with HHV-6 at the time of their death. However, it remains unclear when in the course of the human immunodeficiency virus (HIV) infection the active HHV-6 infection first appears. To address this question, lymph node biopsies from 10 HIV-infected patients were analyzed for active human herpesvirus 6 (HHV-6) infections by immunohistochemical staining. Eight of the biopsies carried the histologic diagnosis of follicular hyperplasia; the other two were characterized as having follicular involution with histiocytosis and reactive lymphadenitis. In total, 10 of 10 (100%) of the lymph nodes studied contained cells productively infected with HHV-6; in contrast, three lymph nodes with follicular hyperplasia and four normal lymph nodes from patients not infected with HIV were negative for HHV-6 infection. Of special note, the absolute CD4+ lymphocyte counts of 75% (6/8) of the HIV-infected individuals included in these studies were > 200/mm3 at the time of their lymph node biopsy. The A variant of HHV-6 was found to be the predominant form of the virus present in the lymph node biopsies from all of these HIV-infected patients, and in vitro studies demonstrated that exposure of monocytic cells carrying latent HIV to HHV-6A resulted in massive upregulation of HIV replication from latency. Thus, active HHV-6 infections appear relatively early in the course of HIV disease, and in vitro studies suggest that the A variant of HHV-6 is capable of breaking HIV latency, with the potential for helping to catalyze the progression of HIV infections to AIDS.

Variant B human herpesvirus-6 associated febrile dermatosis with thrombocytopenia and encephalopathy in a liver transplant recipient.

Human herpesvirus 6 (HHV-6) is a recently discovered virus the pathogenicity of which in solid organ transplant recipients has not been defined. We describe a unique febrile syndrome due to disseminated invasive variant B HHV-6 infection in a liver transplant recipient with evidence of direct tissue invasion by the virus. Acute febrile illness characterized by life-threatening thrombocytopenia, progressive encephalopathy and skin rash developed in association with invasive HHV-6 infection in a liver transplant recipient. HHV-6 was isolated from the patient's peripheral blood in cell culture; variant B HHV-6 DNA was detected in the patient's peripheral blood mononuclear cells (PBMC) at a concentration greater than 1000 virus genomes per 10(6) PBMC. A bone marrow biopsy was also positive for HHV-6, documenting direct tissue invasion. Intravenous ganciclovir for three weeks led to a prompt clinical response. Although larger studies are warranted, our case suggests that HHV-6 should be considered in the diagnostic evaluation of patients with fever, cytopenia, and encephalopathy, particularly since HHV-6 is susceptible to ganciclovir and foscarnet.

Chronic myelopathy associated with human herpesvirus-6.

Human herpesvirus-6 (HHV-6) is implicated in a variety of neurologic diseases. We report a previously healthy elderly woman with progressive spastic paraparesis. At autopsy the spinal cord showed widespread demyelination, axonal loss, and chronic inflammation. HHV-6 DNA was amplified, using polymerase chain reaction, from spinal cord tissue, and glial cells were immunoreactive with an HHV-6 antibody. These findings suggest that HHV-6 may cause myelopathy.

Late graft failure due to dual bone marrow infection with variants A and B of human herpesvirus-6.

Hematopoietic effects of human Herpesvirus-6 (HHV-6) infection following bone marrow transplantation (BMT) include delayed engraftment and early myelosuppression. Variant A has not been isolated after BMT. A case of graft failure is reported following an HLA-identical BMT for chronic myelogenous leukemia (CML) in chronic phase. Evaluation of bone marrow during the period of graft failure revealed variants A and B of HHV-6 by culture, immunofluorescence, polymerase chain reaction (PCR), and immunohistochemistry. Evidence for other cases of graft failure, including cytomegalovirus (CMV), could not be found. A hypothesis is proposed that late graft failure in this case was due to variant A of HHV-6.

Active human herpesvirus (HHV-6) infection of the central nervous system in patients with AIDS.

White matter disease is a relatively common neuropathological change observed in the central nervous system (CNS) tissues of patients with AIDS at autopsy. This disease ranges from small foci of myelin loss to extensive areas of demyelination. In the studies reported here, four of six unselected adult patients with AIDS had areas of demyelination in their CNS tissues at the time of their deaths. In the tissues examined, the severity of the demyelinative disease varied among the patients from a single focus of demyelination to essentially confluent loss of myelin in subcortical white matter and other CNS structures. The demyelinative disease in the brains of these patients was closely associated with active HHV-6 infection. The infected cells were present only in areas of demyelination, and they were never observed in tissue areas free of pathological changes. The HHV-6-associated neuropathology observed in the brains of these patients was identical to that described in an adult bone marrow transplant (BMT) patient with fatal HHV-6 encephalitis. Thus HHV-6-induced white matter disease appears to be a distinct pathological syndrome. Pathogenic mechanisms involved in this disease are unknown. However, the existence of HHV-6 leukoencephalopathy in a BMT patient demonstrates the potential for HHV-6 leukoencephalopathy in a BMT patient demonstrates the potential for HHV-6 to cause this syndrome without need for a cofactor or copathogen such as HIV.