Association of active human herpesvirus-6 (HHV-6) infection with autoimmune thyroid gland diseases

Objectives

Viral infections frequently have been cited as important environmental factors implicated in the onset of autoimmune thyroiditis (AIT). The aim of this study was to determine the involvement of HHV-6 infection in the development of autoimmune thyroiditis.

Heterophil-negative mononucleosis-like illnesses with atypical lymphocytosis in patients undergoing seroconversions to the human immunodeficiency virus

The authors present data from four patients with acute heterophil-negative mononucleosis-like illnesses who were initially thought to have primary Epstein-Barr virus (EBV) infections but eventually were shown to be seroconverting to the human immunodeficiency virus (HIV). Widespread lymphadenopathy and blood smears indistinguishable from those typically encountered in the acute phase of infectious mononucleosis were present in all cases. There were also varying combinations of fever, sore throat, and malaise, as well as mild abnormalities of hepatic function and elevated cold agglutinins (anti-I). Anti-HIV was detected by both enzyme-linked immunosorbent assay and Western blot techniques in all cases, with increasing titers noted in two of three serially studied cases. In one patient, a dual infection with the hepatitis B virus was also documented. Diagnostic possibilities in patients with acute mononucleosis-like illnesses dominated by prominent lymphadenopathy should include primary seroconversions to HIV.     

Human cytomegalovirus, human herpesvirus-6 and human herpesvirus-7 in neutropenic patients with fever of unknown origin

Objective  To investigate the appearance of cytomegalovirus (CMV) DNA, human herpesvirus-6 (HHV-6) DNA and human herpesvirus-7 (HHV-7) DNA in plasma as a sign of reactivation and possible causes of fever of unknown origin (FUO) during neutropenia.
Methods  From 134 patients with febrile neutropenia following cytotoxic chemotherapy during the years 1996–2000, 20 severely neutropenic patients (granulocyte count < 0.1 × 10⁹/L) were selected. Ten were patients with bacteremia and ten were patients with FUO. Five samples from each patient were selected at the start of chemotherapy, at the time of blood culture and fever, after 24 and 48 hours of fever, and, finally, after two to three days without fever. Virus DNA was detected by real-time quantitative and nested polymerase chain reaction (PCR).
Results  CMV-DNA was detected in two out of ten FUO-patients in all samples drawn during fever. From another FUO and during two bacteremia episodes, CMV-DNA was detected after 48 hours of fever. DNA from HHV-6 and HHV-7 was not detected in any of the 20 febrile episodes.
Conclusions  HHV-6 and HHV-7 as a possible explanation for FUO in severely neutropenic patients treated with cytotoxic chemotherapy seems not be very likely. However, CMV was identified in 5/20 patients and the febrile episodes in the two FUO-patients with constant DNA-emia may have been caused by a reactivation of CMV. This implies that CMV infection can be expected not only in transplant patients but also in chemotherapy-treated neutropenic patients.     

High incidence of cytomegalovirus, human herpesvirus-6, and Epstein-Barr virus reactivation in patients receiving cytotoxic chemotherapy for adult T cell leukemia

The etiology of cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and Epstein-Barr virus (EBV) reactivation and the potential for complications following cytotoxic chemotherapy in the absence of allogeneic transplantation are not clearly understood. Patients with adult T cell leukemia (ATL) are susceptible to opportunistic infections. In this study, the incidence, kinetics and clinical significance of reactivation of CMV, HHV-6, and EBV in ATL patients were investigated. Viral DNA in a total of 468 plasma samples from 34 patients was quantified using real-time PCR. The probability of CMV, HHV-6, and EBV reactivation by 100 days after the start of chemotherapy was 50.6%, 52.3%, and 21.6%, respectively. Although most CMV reactivations were self-limited, plasma CMV DNA tended to persist or increase if the CMV DNA levels in plasma reached ≥ 10(4) copies/ml. CMV reactivation was negatively associated with survival, but the P-value for this association was near the borderline of statistical significance (P=0.052). One patient developed fatal interstitial pneumonia concomitant with peak CMV DNA accumulation (1.6 × 10(6) copies/ml plasma). Most HHV-6 and EBV reactivations were self-limited, and no disease resulting from HHV-6 or EBV was confirmed. HHV-6 and EBV reactivation were not associated with reduced survival (P=0.35 and 0.11, respectively). These findings demonstrated that subclinical reactivation of CMV, HHV-6, and EBV were common in ATL patients receiving chemotherapy. There were differences in the viral reactivation patterns among the three viruses. A CMV load ≥ 10(4) copies/ml plasma was indicative of subsequent exacerbation of CMV reactivation and developing serious clinical course.     

IgG antibodies to human herpesvirus-6 in children and adults and in primary Epstein-Barr virus infections and cytomegalovirus infections [corrected

Antibody titers against human herpesvirus-6 (HHV-6) were determined in 80 healthy adults and 100 children and teenagers from Sweden to gain information on the role of the virus and its epidemiology. Based on a positive immunofluorescence titer of 1:10 and above, about 85% of the adults and children were seropositive with 60% seropositivity of children below age one year. Titers were generally higher in patients with simultaneous EBV or CMV infection, yet crossreactivity appeared essentially no problem. HHV-6 thus is ubiquitous like other herpesviruses. Primary infection seems to occur early in life, and reactivation or delayed primary infection may be associated with a variety of disorders.     

Lymphadenopathy in connection with human herpes virus type 6 (HHV-6) infection

Summary Two siblings and their mother developed afebrile generalized lymphadenopathy. The lymph nodes were movable and painless. During the course of the illness, the mother and one child developed an uncharacteristic rash. Increased titers of human herpes virus type 6 (HHV-6) antibodies were found in all three family members and in an unrelated patient with lymphadenitis colli. The enlarged lymph nodes decreased in size within several weeks. We speculate these symptoms to be caused by an infection with this lymphotropic virus.     

Human herpesvirus-6 (HHV-6, HBLV) in sarcoidosis and lymphoproliferative disorders

Serologic studies were done to estimate the antibody prevalence against human herpesvirus 6 (HHV-6) in patients with malignant lymphomas, Sj?gren's syndrome and sarcoidosis. Serologic studies showed IgG antibody titers against HHV-6 in up to 41% of patients with sarcoidosis, 50-70% with malignant lymphomas and in 36% with Sj?gren's syndrome. In situ hybridization on lymph node biopsies was positive for HHV-6 genome in 1 out of 5 sarcoidosis lymph nodes.     

Significance of Epstein-Barr virus (HHV-4) and CMV (HHV-5) infection among subtype-C human immunodeficiency virus-infected individuals

Purpose: Opportunistic viral infections are one of the major causes of morbidity and mortality in HIV infection and their molecular detection in the whole blood could be a useful diagnostic tool. Objective: The frequency of opportunistic DNA virus infections among HIV-1-infected individuals using multiplex real-time PCR assays was studied. Materials and Methods: The subjects were in two groups; group 1: Having CD4 counts <100 cells/µl (n = 118) and the group 2: counts >350 cells/µl (n = 173). Individuals were classified by WHO clinical staging system. Samples from 70 healthy individuals were tested as controls. In-house qualitative multiplex real-time PCR was standardised and whole blood samples from 291 were tested, followed by quantitative real-time PCR for positives. In a proportion of samples genotypes of Epstein-Barr virus (EBV) and CMV were determined. Results: The two major viral infections observed were EBV and CMV. The univariate analysis of CMV load showed significant association with cryptococcal meningitis, oral hairy leukoplakia (OHL), CMV retinitis, CD4 counts and WHO staging (P < 0.05) while the multivariate analysis showed an association with OHL (P = 0.02) and WHO staging (P = 0.05). Univariate analysis showed an association of EBV load with CD4 counts and WHO staging (P < 0.05) and multivariate analysis had association only with CD4 counts. The CMV load was significantly associated with elevated SGPT and SGOT level (P < 0.05) while the EBV had only with SGOT. Conclusion: This study showed an association of EBV and CMV load with CD4+ T cell counts, WHO staging and elevated liver enzymes. These viral infections can accelerate HIV disease and multiplex real-time PCR can be used for the early detection. Genotype 1 and 2 of EBV and genotype gB1 and gB2 of CMV were the prevalent in the HIV-1 subtype C-infected south Indians.     

Antibody prevalence to HBLV (human herpesvirus-6, HHV-6) and suggestive pathogenicity in the general population and in patients with immune deficiency syndromes

Detailed serologic screening showed an antibody prevalence to HBLV (HHV-6) in the general population of 26% if very strict criteria for antibody positivity were applied. Lower and borderline antibody titers yet may be found in up to 63% of the population. Only 17% of these persons have clinical symptoms; in the majority infection remains silent. HHV-6 infection apparently occurs already quite early in life, and initial symptoms can occur, such as short-term high fever, sore throat, local lymphadenopathy and skin rash. Lesions disappear without specific treatment. The frequency of positive antibody tests at higher titers rises in patients with immune deficiency and with atypical lymphoproliferative diseases to 60 and 75%. The rise in antibody titers is associated in patients with immune deficiency by characteristic shifts of blood lymphocyte populations, essentially by increase in immature T-lymphocytes. Highest titers are found in patients with lymphoproliferative syndromes, yet the percentage of atypical lymphoid cells harboring the viral genome is low (about 2% of seropositive patients). Thus it appears, that HBLV, similar to other herpesviruses such as Epstein-Barr virus, usually causes a silent seroconversion, yet may be associated with variable clinical pathology when persisting in an active state. Its pathogenic effect might be rather a cofactor contributing to immune disturbance than overt oncogenicity.     

Centrifugal enhancement of human immunodeficiency virus (HIV) and human herpesvirus type 6 (HHV-6) infection in vitro

The effect of centrifugal inoculation of human immunodeficiency virus (HIV) and human herpesvirus-6 (HHV-6) on the infectivity of the viruses for cell cultures was examined. Three HIV-1 strains, ARV-2, HTLV-IIIb and a local isolate, WA-46c, were tested in peripheral blood lymphocytes, HUT-78, H9 and MT-2 cells. The HHV-6 strain was a local isolate and was studied only in peripheral blood lymphocyte cultures. Centrifugal inoculation of the viruses at a force of 2500 x g for 60 min, enhanced HIV-1 infectivity by a factor of about 10-fold in all cell cultures tested. Infectivity was increased about 100-fold for HHV-6.     

Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases

BackgroundLittle is known about the involvement of human herpesviruses 6 and 7 (HHV-6 and HHV-7) in autoimmune connective tissue diseases (ACTD).ObjectiveTo determine the prevalence of active infection with HHV-6 and HHV-7 in patients with ACTD.Study designThe presence and quantity of HHV-6 DNA was determined by quantitative real-time PCR in a cross-sectional study of serum, peripheral blood mononuclear cells, and tissues obtained from 58 ACTD patients and 38 healthy subjects (HS). Specific anti-HHV-6 antibody titer was also measured.ResultsHHV-6 serum viremia occurred in a significantly higher proportion of ACTD patients compared to HS [26/58 (44.8%) vs. 1/38 (2.6%), p = 0.001] with the highest reactivation frequency [7/10 (70%)] observed in patients with scleroderma. Moreover, HHV-6 in serum was associated with ACTD activity (22/38 vs. 4/20, p < 0.05). Higher titers of HHV-6 antibodies were found in ACTD patients than in HS, although HHV-6 seroprevalence among patients with ACTD and HS was similar. HHV-7 viremia was not detected in any patients or HS controls.ConclusionThe frequent reactivation of HHV-6 in scleroderma and other ACTD, especially when active, suggests that HHV-6 may play a role in the pathogenesis of these diseases.     

Relevance of clinical and laboratory findings in the diagnosis of cytomegalovirus encephalitis in patients with AIDS

A retrospective evaluation was conducted in patients with AIDS and an autopsy diagnosis of cytomegalovirus (CMV) encephalitis to determine the relevance of clinical and laboratory findings in establishing a diagnosis. On autopsy of 100 patients, CMV encephalitis was diagnosed in 13 patients; eight had periventricular CMV encephalitis, four micronodular CMV encephalitis, and one both conditions. Seven patients had had a CMV infection previously (6 cases of retinitis, 1 case of colitis), and at the onset of encephalitis all of them were receiving a maintenance dose of ganciclovir. Examination of the CSF showed specific changes in patients with periventricular encephalitis. CT revealed no characteristic findings, while MRI showed an increased signal intensity on T2 weighted images. CMV DMA amplification by nested PCR was performed in nine patients with CMV encephalitis; PCR was positive in eight patients whose CSF was collected during CMV encephalitis, and negative in one patient whose CSF was collected six months before death. In conclusion, some clinical findings suggest a presumptive diagnosis, especially of periventricular encephalitis, and nested PCR appears to be a reliable and rapid technique for making an antemortem diagnosis.     

Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections

Human herpesvirus 6 (HHV-6) is a ubiquitous virus inducing a life-long latent infection of its human host. Acute infections (AIs) have been recognized as the cause of severe diseases. These AIs correspond to primary infections (PIs), mainly occurring in young children, endogenous reactivations (ENRs), observed at any age, and putative exogenous reinfections (EXRs). The diagnosis of AIs is now essentially based on the quantification of viral load in bodily fluids and organs by means of real time PCR. However, this diagnosis is currently bothered by the lack of well established viral load thresholds for the different levels of virus replication, the concomitant infection with the two variants HHV-6A and HHV-6B, and the existence, albeit at low frequency, of chromosomal integration of viral DNA. An additional challenge is the difficulty to establish the causality relationship between AI and disease. Although many AIs are asymptomatic or poorly symptomatic with a spontaneous favourable outcome, some have been credited with serious clinical manifestations affecting central nervous system, liver, gastrointestinal tract, lungs, and bone marrow. The main favouring factor for such serious diseases is cellular immune deficiency. These severe diseases can be exemplified by encephalitis cases either associated with PI in young children or with ENR, especially in haematopoietic stem cell transplant recipients. The antiviral drugs ganciclovir, foscarnet and cidofovir have proven to be efficient against AIs and related diseases but the indications and conditions of their use are not yet formally approved. This emphasizes the need for controlled studies addressing both the clinical impact and therapy of HHV-6 AIs.     

Human herpes virus type 6 (HHV-6) and its in vitro effect on human immunodeficiency virus (HIV).

Human herpes virus type 6 (HHV-6) was isolated from the peripheral blood lymphocytes of a patient infected with human immunodeficiency virus (HIV). Antibodies to this herpes virus were found to be widespread among adults and children in Western Australia. Co-infection studies indicated that HIV replication was inhibited by the presence of HHV-6.     

HHV-6 A- or B-specific P41 antigens do not reveal virus variant-specific IgG or IgM responses in human serum.

The etiology of multiple sclerosis (MS) remains unknown, but there are indications of a role of human herpesvirus 6 (HHV-6), especially variant A, in the pathogenesis. Higher serum antibody reactivity against an HHV-6 early protein, p41, has been found in MS cases than in controls. The antigen, however, was purified from infected cells with a monoclonal antibody also reactive with a protein (p38) likely to be of cellular origin. To avoid serological crossreactivity with the cellular protein, recombinant p41 proteins from HHV-6A strain GS and HHV-6B strain Z29 were expressed as glutathione-S-transferase fusion proteins (p41-GST), and used as antigens in an enzyme-linked immunosorbent assay (ELISA). p41 variant specific monoclonal antibodies reacted strongly with the respective recombinant proteins. Serum IgM and IgG reactivities with the recombinant p41 antigens were analysed in patients with manifest MS, patients with optic neuritis, patients with other neurological diseases, and in one group of healthy controls. All sera were HHV-6 IgG seropositive by immunofluorescence. The serum IgM or IgG reactivities against the recombinant p41 antigens did not differ significantly between the groups, and the reactivities against the variant A and B antigens were identical. In many samples, the reactivity was very low. The results indicate that p41 is not an optimal target for HHV-6 serology studies, and that the data obtained with the p41 antigen prepared from infected cells (possibly including also p38) should be interpreted with caution.     

Simultaneous infection with human herpesvirus-6 and measles virus in infants

Two infants (4 and 5 months of age) with a febrile episode for 3 and 5 days, respectively, developed skin rashes after the fever subsided and were diagnosed as exanthem subitum. The rash continued for 5 days followed by mild-to-moderate pigmentation. Human herpesvirus-6 and measles virus, which were confirmed by a specific immunofluorescence assay and by electron microscopy, were isolated simultaneously from blood in the acute stage of the disease but not from the convalescent stage. The titer of the herpesvirus-6 in blood was greater than that of measles. Specific serologic assays showed marked seroconversion against human herpesvirus-6 but not to measles virus. The results suggest that dual infection with human herpesvirus-6 and measles virus results in atypical exanthem subitum or modified measles with unique immunologic responses.     

Epidemiology of human herpes virus 8 (HHV-8) or the herpes virus associated with Kaposi's sarcoma (KSHV)

Human herpesvirus 8 (HHV-8), also called Kaposi's sarcoma-associated herpesvirus (KSHV), is not a ubiquitous virus. In countries with a low viral seroprevalence (< 5% in adult general population) as the USA, Northern Europe and Asia, the infection concerns essentially homosexual men. In this latter population, the viral transmission seems to occur during sex. In endemic countries (HHV-8 seroprevalence between 10-70% in the adult general population) as in the Mediterranean basin (Italy, Greece), and Africa (East and Central Africa), men, women and children are infected. In these countries, HHV-8 seroprevalence increases with age and often reaches adult rates before the end of puberty. Viral transmission, in general endemic populations, seems to occur from mother to child and between sibs whereas heterosexual transmission appears to concern essentially groups at risk for sexual transmitted diseases. Saliva is a major reservoir of HHV-8.     

Herpes simplex virus, cytomegalovirus and Epstein-Barr virus antibody titres in sera from schizophrenic patients

Serum antibody titres to herpes-simplex (HSV-1, 2), cytomegalovirus (CMV), and Epstein-Barr virus capsid antigen (EBV-VCA) were determined in 38 unrelated chronic schizophrenic patients, 11 nuclear families with at least 2 schizophrenic members, and 2 control groups. The distributions of antibody titres to herpes simplex and cytomegalovirus were similar among all groups. Patients had higher anti-EBV-VCA titres than non-hospitalized controls; however, hospital staff members in contact with the patients also had significantly higher antibody titres to EBV-VCA. Antibodies to EBV early antigen (EBV-EA) were also determined for 27 unrelated patients and 24 mental hospital employees. The schizophrenic patients had significantly higher antibody titres to EBV-EA than the hospital worker control group. These data do not support the hypothesis that herpes viruses are associated with the aetiology of schizophrenia. Although elevated anti-EBV early antigen titres may suggest persistent active EBV infection, it is unlikely to be related to the aetiology of the disorder, since discordance for EBV seropositivity was present among sibling pairs concordant for schizophrenia.     

Frequent detection of Epstein-Barr Virus and cytomegalovirus but not JC virus DNA in cerebrospinal fluid samples from human immunodeficiency virus-infected patients in northern Thailand

Applying nested-PCRs, we frequently detected DNA of Epstein-Barr virus and cytomegalovirus but not JC virus in cerebrospinal fluid samples from 140 human immunodeficiency virus-infected patients with central nervous system symptoms in northern Thailand. Despite the low incidence of primary central nervous system lymphoma or cytomegalovirus encephalitis among Thai AIDS patients, Epstein-Barr virus and cytomegalovirus infections in the central nervous system are common.