Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay. Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1ß, suggesting a disturbance in interleukin 1 signaling. Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

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.

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.

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.

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.

Fulminant human herpesvirus six encephalitis in a human immunodeficiency virus-infected infant.

Self-limited involvement of the central nervous system (CNS) is a relatively common complication of primary infection with human herpesvirus six (HHV-6) in normal children. We describe an HIV-infected infant who developed fulminant encephalitis as a complication of HHV-6 infection. Immunohistochemical staining of CNS tissue demonstrated productive infection of all CNS cell-types. Analysis of the infected brain tissue by the polymerase chain reaction (PCR) confirmed the presence of a dense HHV-6 infection in the tissue, and demonstrated that the virus present in the CNS tissue was predominantly the A variant of HHV-6. This is the first demonstration of invasive tissue disease caused by HHV-6 in an HIV-infected infant.

Progressive immunodeficiency and fatal pneumonitis associated with human herpesvirus 6 infection in an infant.

Human herpesvirus 6 (HHV-6), an important opportunistic pathogen in immunocompromised patients, causes fatal pneumonitis, encephalitis, and bone marrow suppression. Its ability to infect and destroy T lymphocytes may allow it to synergize with the human immunodeficiency virus in the destruction of lymphoid tissues in patients with AIDS. We describe herein an infant who had an immunodeficiency associated with thymic atrophy and severe T lymphocytopenia who developed fatal pneumonitis due to HHV-6. Dense and disseminated infection of T lymphocytes with HHV-6 was also documented. In the absence of any other documented cause of immunodeficiency, we hypothesize that congenital infection of this infant with HHV-6 may have caused progressive destruction of her cellular immune system, leading to the fatal pneumonitis. Thus, HHV-6 infection may have been the cause of both her immunodeficiency and her fatal opportunistic infection.

Human herpesvirus 6 (HHV-6) isolation from bone marrow: HHV-6-associated bone marrow suppression in bone marrow transplant patients.

These studies tested the hypothesis that human herpesvirus 6 (HHV-6) can cause posttransplant bone marrow (BM) suppression in BM transplant (BMT) patients. Fifteen adult patients who received T-lymphocyte-depleted, allogeneic BM transplants and who developed posttransplant BM suppression were studied. Detailed chart reviews were used to divide the patients into two groups: (1) those with diagnosed BM suppression (DBMS) and (2) those with idiopathic BM suppression (IBMS). BM aspirates obtained from the patients at the onset of BM suppression were subjected to an HHV-6 isolation procedure using mitogen-stimulated blood mononuclear cells. BM specimens obtained from another population of BMT patients solely to document engraftment irrespective of their BM function were also subjected to the HHV-6 isolation procedure as controls. HHV-6 was isolated from 6 of 15 BM samples from BMT patients with BM suppression. BM samples from patients with IBMS were more likely to be positive for HHV-6 than those from patients with DBMS (P < .01). Also, HHV-6-positive BM were significantly more likely (P < .05) to come from patients with suppression of more than one BM lineage than HHV-6-negative BM. Finally, samples of BM from an unselected series of BMT patients studied without regard to their BM function were less likely (P < .01) to be positive for HHV-6 than patients with IBMS.

Human herpesvirus-6-associated malignant lymphoma in a bone marrow transplant recipient.

BACKGROUND: Human herpesvirus-6 (HHV-6), the sixth member of the herpesvirus family, can infect and replicate in human hematopoetic cell lines and can cause various illnesses in humans. HHV-6 has been suggested to be linked to various lymhoproliferative disorders. In vitro studies have demonstrated the oncogenic potential of HHV-6. The role of HHV-6 in human lymphomas needs to be examined. OBJECTIVE: To determine the involvement of HHV-6 in an immunoblastic lymphoma which developed in a bone marrow transplant patient, who had HHV-6 viremia. STUDY DESIGN: Paraffin-embedded lymphoma tissues were examined for the presence of HHV-6 by immunohistochemistry, PCR and in-situ hybridization. This is a case report investigation. RESULTS: An acute myelogenous leukemia patient received an allogeneic bone marrow transplant. He developed human herpesvirus-6 (HHV-6) viremia approximately 6 weeks after transplantation and HHV-6 was concurrently isolated from his bone marrow. Soon afterward, a large cell immunoblastic lymphoma was diagnosed. Complications of this tumor subsequently resulted in the patient's death. Periaortic lymph nodes and tumor cells infiltrating the liver and kidneys showed the presence of HHV-6 by immunohistochemistry and polymerase chain reaction (PCR). Southern blot analysis of the PCR amplified DNAs confirmed the presence of transforming pZVH14 DNA sequences of HHV-6 in the tumor tissues. Lymph nodes of 6 immunologically intact individuals were negative for HHV-6 by immunohistochemistry and PCR analysis. Tumor tissues were negative for EBV DNA by in situ hybridization with DNA probes specific for the EBV EBER RNAs. CONCLUSION: Our data suggest that HHV-6 may be involved in the pathogenesis of some immunoblastic lymphomas.