Human herpesvirus 6 and human herpesvirus 7: emerging pathogens in transplant patients

Human herpesvirus 6 (HHV-6) and HHV-7 are two recently identified beta-herpesviruses, genetically related to human cytomegalovirus (CMV). Infection with both viruses is common worldwide with rates of seropositivity in adults over 90%. Infection with both viruses usually occurs in early childhood. In this age group HHV-6 is a cause of febrile illness including exanthem subitum, and likewise, primary HHV-7 infection has been associated with febrile illness. Similar to the other human herpesviruses, in particular CMV, the viruses have the potential for enhanced pathogenicity in the immunocompromised host. Active infection with both viruses is common following bone marrow or solid organ transplantation, most likely through reactivation of recipient's virus or re-infection considering their high prevalence in the population. Both viruses can be detected by PCR in the peripheral blood of healthy individuals and although the significance of blood-borne transmission is not clear, a preliminary study suggested that it was not significant for HHV-6. However, there is growing evidence that these viruses may be medically important in the post-transplant period. In bone marrow transplant patients HHV-6 has been associated with a range of clinical disease including encephalitis, interstitial pneumonitis, early and late graft failure and bone marrow suppression. There is also growing evidence for potential interactions among the beta-herpesviruses in liver and renal transplant patients. HHV-6 infection has been associated with an increased risk of developing CMV disease and opportunistic infections and HHV-7 infection has also been linked to an increased risk of CMV disease.     

Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients.

To determine whether receipt of an investigational anti-CD3 monoclonal antibody (BC3) increased the risk of human herpesvirus 6 (HHV-6) reactivation and development of encephalitis in bone marrow transplant (BMT) recipients, persons who had and had not received BC3 were compared. Odds of HHV-6 reactivation were higher among BC3 recipients than among control patients (odds ratio, 2.5; 95% confidence interval [CI], 1.3-4.7). In addition, BC3 recipients were more likely than control patients to develop encephalitis (risk ratio [RR], 3.5; 95% CI, 1.3-9.5), and this association followed a BC3 dose-dependent relationship (P=.03, by Mantel-Haenszel chi(2) test). In a multivariable model, HHV-6 reactivation and receipt of BC3 were associated with increased risk of encephalitis (RR, 5.4; 95% CI, 1.9-15.3, and RR, 3.3; 95% CI, 1.2-9.1, respectively). In conclusion, both HHV-6 reactivation and receipt of BC3 for prophylaxis of acute graft-versus-host disease independently increased the risk of encephalitis in allogeneic BMT recipients. Prospective studies to better define the relationship between HHV-6 reactivation and encephalitis in allogeneic BMT recipients are warranted.     

Human herpesviruses 6 and 7 in solid organ transplant recipients.

The impact of cytomegalovirus, a member of the beta-herpesvirus subgroup of the Herpesviridae, on patients who have undergone transplantation cannot be overstated. However, in the last 15 years, 2 additional members of the human beta-herpesvirus family have been discovered: human herpesviruses 6 and 7 (HHV-6 and HHV-7). The impact of HHV-6 and HHV-7 is assessed, as is the well-being of transplant recipients. Also discussed is whether the data on the pathological consequences of infection warrant routine screening for these viruses in solid organ transplant recipients.     

Human herpesvirus 6 infection and cytomegalovirus-specific lymphoproliferative responses in allogeneic stem cell transplant recipients

The aim of this study was to investigate the effects of HHV-6 DNAemia on the CMV specific lymphoproliferative response after allogeneic stem cell transplantation. Twenty-one allogeneic stem cell transplantation (allo-SCT) patients were included in the study. The patients were either CMV seropositive and/or had CMV seropositive donors. We studied the effects of HHV-6 infection, documented by PCR, on CMV-specific lymphocyte proliferation response and on CMV infection documented by PCR. HHV-6 DNAemia correlated with the absence of CMV-specific lymphocyte proliferation responses after allo-SCT. Three of nine patients with persistent HHV-6 DNA had a CMV-specific lymphocyte proliferative response compared to 11 of 12 patients without persistent HHV-6 DNAemia (P = 0.02). Patients with higher HHV-6 DNA levels (>100 copies) were more likely than those with lower copy numbers not to develop a CMV-specific immune response (six of nine vs one of eight; P < 0.05). Patients who were repeatedly HHV-6 positive in three or more consecutive blood samples were also more likely to need repeated courses of preemptive antiviral therapy against CMV during the first 6 months after transplantation (P < 0.001). Our data indicate the possibility that HHV-6 can suppress the development of CMV-specific immune responses and thereby could predispose to development of late CMV disease.     

Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors

Human herpesvirus 6 (HHV-6) infection was studied in 82 bone marrow transplant (BMT) recipients (72 allogeneic, 10 autologous). All recipients and 30 donors were seropositive for HHV-6 antibody at the time of bone marrow transplantation. Thirty-one recipients (37.8%) had HHV-6 viremia 2-4 weeks after transplantation. The incidence of HHV-6 viremia was significantly higher among allogeneic BMT recipients than in autologous BMT recipients (P=.011). Therefore, the following analyses of allogeneic BMT recipients were carried out (n=72). Geometric mean antibody titers (log(10)) were significantly higher in recipients without viremia than in those with viremia (1.84+/-0.39 vs. 1.61+/-0.42; P=.022). Logistic regression analysis demonstrated that leukemia or lymphoma is an independent risk factor (P=.031) for HHV-6 viremia. Rash occurring within 1 month after transplantation was observed in 17 (54.8%) of 31 recipients with HHV-6 viremia but in only 8 (19.5%) of 41 recipients without HHV-6 viremia (P=.001).     

Human herpesvirus type 7 in Hodgkin's disease

Several lines of evidence have pointed to the involvement of a viral agent in the pathogenesis of Hodgkin's disease (HD). Therefore we investigated the presence of human herpesvirus type 7 (HHV-7) in 53 cases of HD by polymerase chain reaction (PCR), DNA in situ hybridization (ISH) and immunohistochemistry. HHV-7 DNA was frequently detected (68% of the cases) in HD biopsies by PCR independently of the histological type, whereas only 32% ( P  < 0.05) of positive cases were found in 19 reactive lymph nodes. However, by applying the quantitative PCR technique, the majority of the samples showed a low level of viral load. Moreover, ISH for HHV-7 DNA was positive in a low number of small T lymphocytes and consistently negative in Hodgkin and Reed-Sternberg (HRS) cells, which appeared negative for HHV-7 also at immunohistochemistry.   These results indicate that the high frequency of HHV-7 infection in HD: (i) is probably non-productive, (ii) mainly involves small lymphocytes belonging to the T-lineage, and (iii) is probably due to the recruitment of non-malignant reactive cells in HD tissue.     

Human herpesvirus type 6: review.

Human herpesvirus type 6 (HHV-6), a newly recognized human herpesvirus first described in 1986, is morphologically similar to other herpesviruses but is distinguishable from all of them by some unique in vitro biological effects, specific antigenic analysis, and patterns of endonuclease restriction digests of DNA. In vitro HHV-6 exhibits tropism mainly for T lymphocytes, but it also infects other cells, including B lymphocytes, monocytes-macrophages, glial cells, and fibroblasts. Because HHV-6 causes frequent infection in infants and children, a seroprevalence rate of antibody to this virus of up to 80% has been reported in the United States. Infection in infancy develops as levels of maternal antibody wane, thus resulting in either subclinical infection or an acute febrile illness termed exanthema subitum. Primary infection acquired later in life causes a disease resembling acute infectious mononucleosis. Since HHV-6 shares the capacity to establish latent infection with other herpesviruses, frequent viral reactivation is probably the explanation for the high incidence of serologically proven active HHV-6 infection found simultaneously with active infection due to other herpesviruses as well as in the presence of various immune deficiency conditions.     

Human herpesvirus 6 antigenaemia in allogeneic stem cell transplant recipients: impact on clinical course and association with other beta-herpesviruses

Human herpesvirus 6 (HHV-6) antigenaemia was prospectively studied in 58 adult allogeneic stem cell transplant (SCT) recipients. Altogether 42 of 58 recipients (72%) demonstrated HHV-6 specific antigens in peripheral blood mononuclear cells after SCT, 22 of 36 (61%) when the donor was a sibling and 20 of 22 (91%) when the donor was unrelated. The cumulative incidence of HHV-6A, HHV-6B, HHV-7, and cytomegalovirus antigenaemia during the first 6 months after SCT was 33%, 62%, 44% and 63% respectively. The median day of the onset of each antigenaemia was +24, +4, +59, and +46 after SCT respectively. There were no clinical findings related to HHV-6A and HHV-7 antigenaemias. A rash was diagnosed in 10 of 38 (26%) HHV-6B antigenaemia positive patients during the first month after SCT compared with one of 20 (5%) HHV-6B negative patients. Of the HHV-6B antigenaemia cases, six of 10 rashes were treated as acute graft-versus-host disease (GVHD) and four of 10 were considered to be of a viral origin. Fifteen patients had acute GVHD diagnosed. Acute GVHD manifested statistically significantly (P = 0.034) earlier in the nine patients with HHV-6B antigenaemia compared with the six patients who were HHV-6B negative.     

Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients

Human herpesvirus-6 (HHV-6) may be a risk factor for cytomegalovirus (CMV) disease in posttransplant patients, possibly through a direct interaction or through a general immunomodulatory effect. To examine this possibility, 88 liver transplant recipients were monitored with serial HHV-6 polymerase chain reaction (PCR), CMV antigenemia, and CMV plasma viral load. HHV-6 infection was defined by a positive PCR of peripheral blood lymphocytes. Forty-eight (54.4%) of 88 patients had at least 1 positive HHV-6 PCR. CMV recurrence was significantly more common in patients with HHV-6 infection (38/48 patients [79. 2%]), compared with recurrence in those without HHV-6 infection (18/40 patients [45%]; P=.001). Peak CMV viral load was 24, 147+/-6799 copies/mL in patients with HHV-6 infection versus 8391+/-4598 copies/mL in patients without HHV-6 infection (P=.001). Symptomatic CMV disease was more common in patients with HHV-6 infection than it was in those without infection (15/48 patients [31. 3%] vs. 4/10 patients [10.0%]; P=.013). In a multivariate analysis including other risk factors for CMV, HHV-6 infection remained an independent risk factor for CMV disease (P=.013; odds ratio, 7.26; 95% confidence interval, 1.52-34.72). HHV-6 is associated with CMV infection and disease, thus supporting an interaction between these viruses.     

Association of human herpesvirus 6 reactivation with severe cytomegalovirus-associated disease in orthotopic liver transplant recipients.

To explore the possible interaction between human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) in patients who have undergone organ transplantation, stored serum samples from 139 orthotopic liver transplant recipients were tested for HHV-6 immunoglobulin (Ig) G and IgM antibodies. HHV-6 reactivation occurred in 87 patients (62.6%) and was associated with CMV disease (P=.01), severe CMV-associated disease (P=.01), older age (P=.005), and use of muromonab-CD3 (Orthoclone; Orthobiotech) as treatment for rejection (P=.02). Trends for an association between HHV-6 reactivation and invasive fungal disease (P=.12), bacteremia (P=.10), and graft loss (P=.12) were seen. In a multivariate analysis of risk factors for severe CMV-associated disease, HHV-6 reactivation (relative risk [RR], 3.5; 95% confidence interval [CI], 1.2-10.2; P=.02), CMV donor-positive-recipient-negative match (RR, 5.7; 95% CI, 2.5-13.2; P<.001), and elevated serum creatinine level (P<.0001) were independent predictors. HHV-6 reactivation is associated with severe CMV-associated disease in liver transplant recipients.     

Human herpesvirus 6 encephalitis

Human herpesvirus (HHV) 6, the etiologic agent of roseola, is nearly universally acquired during childhood. The virus establishes lifelong infection, including within the central nervous system (CNS), and replicates within several CNS cell types. HHV-6 has been linked to CNS disease during primary infection, including febrile seizures and possibly hippocampal injury. HHV-6 may also be associated with neurologic disease later in life, particularly in transplant patients. Recent reports offer evidence that HHV-6 reactivation may underlie a characteristic limbic encephalitis syndrome following hematopoietic cell transplant; the cardinal features of this syndrome include memory loss, insomnia, electroencephalographic evidence of temporal lobe seizure activity, MRI signal intensity abnormalities of the mesial temporal lobe, and the syndrome of inappropriate release of antidiuretic hormone. HHV-6 DNA is frequently detectable by nucleic acid amplification tests in the cerebrospinal fluid and peripheral blood upon symptom onset, which may provide a screening strategy in high-risk patients. Possible associations of HHV-6 with meningoencephalitis, mesial temporal lobe epilepsy, and multiple sclerosis in apparently immunocompetent hosts are under investigation.     

Human herpesvirus 6.

The development of techniques for the culture of lymphoid cells and the isolation of viruses that infect these cells led to the discovery of human herpesvirus (HHV) 6 in 1986. At the time, HHV-6 was the first new human herpesvirus to be discovered in roughly a quarter of a century, and its isolation marked the beginning of an era of discovery in herpesvirology, with the identification of HHV-7 and HHV-8 (Kaposi's sarcoma-associated herpesvirus) during the following decade. Like most human herpesviruses, HHV-6 is ubiquitous and capable of establishing a lifelong, latent infection of its host. HHV-6 is particularly efficient at infecting infants and young children, and primary infection with the virus is associated with roseola infantum (exanthem subitum) and, most commonly, an undifferentiated febrile illness. Viral reactivation in the immunocompromised host has been linked to a variety of diseases, including encephalitis, and HHV-6 has been tentatively associated with multiple sclerosis. This article discusses the major properties of HHV-6, its association with human disease, and the pathobiological significance of viral reactivation.     

Detection of human cytomegalovirus,human herpesvirus type 6 and human herpesvirus type 7 in urine specimens by multiplex PCR

OBJECTIVES: To develop a sensitive multiplex PCR to detect HCMV, HHV6 and HHV7, to test this PCR on urine specimens sent to the virus diagnostic laboratory and on stored urine samples from HIV-positive patients and their HIV-negative partners and to compare the sensitivity of the multiplex PCR with the diagnostic laboratory's routine service for the detection of HCMV. STUDY DESIGN: Primers specific for each of the three viruses were combined in a multiplex PCR that was then optimised for sensitivity. This PCR was applied prospectively to 413 unselected routine urine specimens over a 1 year period and retrospectively to 258 urine specimens from 63 HIV-positive patients and 10 HIV-negative partners. METHODS: In the prospective study, the multiplex PCR detected 40 specimens positive for HCMV alone, 10 for HHV6, 3 for HHV7 and 3 with a dual infection of HCMV and HHV6. The sensitivity for HCMV was 93.5% by multiplex PCR compared to 28.3% by culture. HHV6 DNA was detected in 6 neonates (2-21 days) and HHV7 DNA in 2 neonates (4 and 20 days). In the retrospective study of HIV patients, HCMV was the most commonly detected virus (55.6%) compared to HHV6 (7.9%) and HHV7 (4.8%). CONCLUSIONS:. The multiplex PCR was significantly more sensitive than non-DNA based procedures for the detection of HCMV. Urine may be a useful non-invasive specimen for the detection of HHV6 and HHV7 and their presence in neonates suggest perinatal transmission or the possibility of in utero infection.