Human herpesvirus 6, 7, and 8

Human herpesvirus 6

The natural history of HHV-6A is unknown. In contrast, HHV-6B infects most children before the age of 3 years and is characterized by fever, respiratory symptoms, diarrhea, and rash. In 25% of patients it causes roseola, an acute febrile illness defined by a maculopapular rash appearing as the fever declines. HHV-6B primary infection is also associated with febrile seizures and possibly epilepsy. Most HHV-6B transmission events are thought to occur via shared saliva early in life. Congenital infection had been estimated to occur in approximately 1% of births, although this is now recognized to be mostly the result of inherited chromosomally integrated HHV-6.

After primary infection, HHV-6B can establish latency in mononuclear cells and serve as a reservoir for endogenous viral reactivation. HHV-6B reactivates in approximately 40% of SOT recipients, typically within 2 to 6 weeks after transplantation or after episodes of rejection when they are receiving increased immunosuppression. HSCT recipients are at greatest risk of reactivation during the peri-engraftment period and after diagnosis of GVHD due to treatment with immunomodulatory medications. Patients receiving cord blood transplant are at an especially increased risk of HHV-6B reactivation, with rates as high as 80% to 90%. HHV-6B has been associated with a number of important outcomes, particularly in allogeneic HSCT recipients, including encephalitis, bone marrow suppression, pneumonitis, GVHD, and mortality. The evidence supports a causal association between HHV-6B and encephalitis, an outcome that is rarely reported in non-HSCT recipients. ^, A more specific entity, HHV-6B posttransplant acute limbic encephalopathy, has been estimated to occur in 0.7% of adult donor HSCT recipients and 9.9% of cord blood transplant recipients in the United States.

Reactivation of HHV-6B has been reported in up to 52% of adults receiving cytotoxic chemotherapy, although the clinical significance remains poorly understood. In pediatric patients, one study found that the incidence of HHV-6 DNA detected in blood rose from 17% at time of diagnosis to 37% during chemotherapy and was associated with fever.

The preferential target cell for HHV-6 is CD4 ⁺ lymphocytes; however, cellular host cells include CD8 ⁺ T lymphocytes, natural killer (NK) cells, macrophages, megakaryocytes, glial cells, and epithelial cells. HHV-6A and -6B establish latency by integrating into the telomere regions of the host chromosomes. When this occurs in a germ cell, it can result in chromosomally integrated HHV-6 (ciHHV-6), which can occur in an estimated 1% of the population. Affected individuals have the HHV-6 genome present in every cell of their body. As a result, affected individuals have persistently detectable HHV-6 viral DNA in tissues, blood, and cerebrospinal fluid (CSF). In addition, viral transcripts and antigens have been demonstrated in immunocompetent and immunocompromised patients with inherited ciHHV-6. ^, More recently, the majority of congenital infections have been shown to be due to ciHHV-6.

When ciHHV-6 is not recognized, it can lead to inappropriate treatment of patients. It is important to note that detection of viral DNA does not correlate with symptoms or signs of disease in patients with ciHHV-6. However, there is some evidence that ciHHV-6 can lead to active viral infection and symptomatic disease in severely immunocompromised patients.

Human herpesvirus 7

Most people become seropositive for HHV-7 at a slightly later age than HHV-6B, typically by 5 years of age. Transmission of HHV-7 is similar to other HHVs, typically through shared saliva. HHV-7 exhibits selective tropism for CD4 ⁺ cells, using the CD4 cell receptor for entry. HHV-7 has been described as slower to replicate than HHV-6 and less lytic, with the cytopathic effects similar to HHV-6 but less pronounced. Salivary glands are the major identified site of persistence and replication.

Similar to HHV-6B, HHV-7 may reactivate in SOT recipients. HHV-7–seropositive pediatric patients have been shown to have a 20% to 60% incidence of HHV-7 DNA detection 2 to 6 weeks after transplant. Most reactivation is brief with minimal viremia. Specific risk factors for reactivation have not been clearly defined. Primary infection can also occur in SOT recipients who were seronegative before transplantation. HHV-7 infections are rarely symptomatic in SOT recipients, but rare cases of tissue-invasive disease have been reported and are often associated with other viral infections, including CMV or EBV.

Human herpesvirus 8

HHV-8 has a broad cellular tropism, including infection of B cells, endothelial cells, macrophages, and epithelial cells. Similar to HHV-6 and HHV-7, primary infection is most often through saliva and can be transmitted from caregivers to children through premastication. It can also be spread through infusion of contaminated blood products. HHV-8 seropositivity rises throughout adolescence and varies geographically. HHV-8 seropositivity is lower in North America compared with countries where it is considered endemic. In Israel, 9% of children and up to 18% of adults are seropositive compared with less than 5% of human immunodeficiency syndrome–negative adults in the United States. HHV-8 seropositivity occurs more often in children whose parents are seropositive, with maternal seropositivity being the most important risk factor.

KS has only rarely been reported in HSCT recipients. KS lesions in transplant recipients can develop as the result of reactivation of latent virus or via transmission of the virus or KS lesions from the allograft. In SOT recipients, most KS (80%) appears to result from reactivation of latent virus. The incidence of KS varies geographically and is dependent on local seroprevalence of HHV-8. KS affects less than 1% of transplant recipients in the United States and has been reported as low as 0.1% in central Europe. In areas of high seroprevalence, KS can account for the majority of posttransplant malignancies . In posttransplant recipients who were previously positive for HHV8, increased immunosuppression can lead to of development of lesions and progression of disease, but no specific regimen is associated with increased risk. The risk of disease decreases with time after transplant. In addition to KS, HHV-8 has also been associated with other malignancies, including primary effusion lymphoma and multicentric Castleman disease, a B-cell lymphoproliferative disease. HHV-8 can also be a trigger for HLH.

Hematopoietic stem cell transplant

The majority of HHV-6B reactivation episodes in HSCT recipients are asymptomatic, transient, do not impact overall survival, and do not require antiviral treatment. HHV-6 has been commonly associated with fever and rash after transplantation, and common hematologic effects associated with HHV-6B infection include delayed platelet engraftment and leukopenia. HHV-6 has also been associated with pneumonitis and hepatitis. There is strong evidence that HHV-6B causes encephalitis, particularly after allogeneic HSCT. In most reports and studies of HHV-6B encephalitis, it is defined as encephalopathy without another cause identified. HHV-6B encephalitis in HSCT recipients presents with symptoms that commonly include confusion and altered consciousness. Other symptoms may also include seizures, amnesia, and syndrome of inappropriate antidiuretic hormone secretion. Laboratory findings may include mild CSF pleocytosis and elevated protein. Distinct imaging findings are medial temporal lobe changes on brain magnetic resonance imaging (MRI). HHV-6B–associated posttransplant acute limbic encephalitis is defined by anterograde amnesia, syndrome of inappropriate antidiuretic hormone, mild CSF pleocytosis, temporal electroencephalogram abnormalities, and MRI hyperintensities in the limbic system.

HHV-7 reactivation is rarely associated with clinical symptoms, although it has been suggested that HHV-7 also can be associated with higher CMV viral loads and delayed clearance of viremia.

HHV-8 reactivation or primary infection after HSCT has rarely been reported in the absence of malignant disease. Studies of the natural history of viral reactivation after HSCT are lacking; other than malignancy, the frequency and outcome of viral reactivation has not been well described. Clinical symptoms described include fever, rash, hepatitis, and bone marrow failure. HHV-8 has rarely been reported to cause KS in HSCT recipients. Symptoms of KS in HCT recipients can include graft failure and pancytopenia in addition to skin lesions. The median time of onset has been reported as 8.5 months after HSCT, and diffuse disease developed in 50% of these patients, with mortality rates reported up to 70%.