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Human herpesvirus 6 infection in hematopoietic cell transplant recipients

Human herpesvirus 6 infection in hematopoietic cell transplant recipients
Literature review current through: Jan 2024.
This topic last updated: Aug 23, 2023.

INTRODUCTION — Human herpesvirus 6 (HHV-6) is a member of the Roseolovirus genus of the beta-herpesvirus subfamily of human herpesviruses. There are two HHV-6 species, HHV-6A and HHV-6B, which have distinct biological properties and genome sequences [1].

The epidemiology, clinical manifestations, diagnosis, and treatment of HHV-6 infections in hematopoietic cell transplant (HCT) recipients will be discussed here. HHV-6 infections in patients who are not HCT recipients are presented separately.

(See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection".)

(See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment".)

(See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults".)

EPIDEMIOLOGY — The vast majority of documented primary infections and reactivation events are due to HHV-6B [2-4]. HHV-6B infects most children within the first three years of life and, like other herpesviruses, it establishes latency after primary infection. HHV-6B may reactivate in immunocompromised hosts, especially following allogeneic HCT. Little is known about the epidemiology or clinical implications of HHV-6A.

The ubiquitous nature of HHV-6B and the fact that it causes latent infection complicate the ability to link disease with the virus. Further complicating this situation is the condition of inherited chromosomally integrated HHV-6, an emerging aspect of HHV-6 biology that remains under study. (See 'Inherited chromosomally integrated HHV-6' below.)

HHV-6B reactivation occurs in 30 to 70 percent of patients undergoing allogeneic HCT [2,5-8], typically between two and four weeks after transplantation. Encephalitis is the most clearly established clinical manifestation of HHV-6B reactivation in allogeneic HCT recipients and, while it may result in substantial morbidity, it occurs in a small subset of these patients.

Risk factors — The type of transplant and related variables have been identified as risk factors for HHV-6B reactivation. As an example, recipients of allogeneic HCT are at higher risk of HHV-6B reactivation than recipients of autologous HCT; among allogeneic HCT recipients, those who receive transplants from unrelated or human leukocyte antigen (HLA)-mismatched donors are at particularly increased risk [7-11]. In addition, myeloablative conditioning has been shown to be a risk factor [8].

The source of stem cells also influences the risk of reactivation; recipients of umbilical cord blood stem cells experience reactivation rates of 70 to 90 percent, compared with rates of 30 to 50 percent in recipients of peripheral blood or bone marrow stem cells [8,10-13].

Younger age, male sex, and underlying disease have variably been identified as pretransplantation risk factors for HHV-6B reactivation occurring after transplantation [2,6], whereas receipt of glucocorticoids has been identified as a post-transplantation risk factor [2,9]. Receipt of an anti-CD3 monoclonal antibody, BC3 (which targets T lymphocytes and has been used for prophylaxis against graft-versus-host disease [GVHD]), has also been associated with an increased risk of HHV-6B reactivation following transplantation [14].

CD134, a member of the tumor necrosis factor (TNF) receptor superfamily, has been identified as a receptor for HHV-6B entry into cells, and its expression levels in CD4+ T cells may play a role in reactivation of HHV-6 following allogeneic HCT [15,16]. In one study, a higher CD134/CD4 ratio before conditioning was associated with a higher risk of HHV-6B reactivation following allogeneic HCT [17]. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection", section on 'Viral replication'.)

Disease associations — HHV-6B is associated with several important complications following HCT, including encephalitis and bone marrow suppression. Associations with other outcomes including GVHD, cytomegalovirus reactivation, pneumonitis, and mortality have been described.

Encephalitis — Case reports and small case series have described encephalitis in HCT recipients with HHV-6B detected in the cerebrospinal fluid (CSF) [18-22], and observational studies have demonstrated an association between systemic HHV-6B reactivation and subsequent encephalitis [5,9]. Taken together, these data support a causal association between HHV-6B infection and encephalitis in allogeneic HCT recipients.

One group has termed the encephalitis associated with HHV-6B in HCT recipients "post-transplant acute limbic encephalitis," describing it as a distinct syndrome of anterograde amnesia, syndrome of inappropriate antidiuretic hormone, mild CSF pleocytosis, temporal electroencephalogram abnormalities often reflecting clinical or subclinical seizures, and magnetic resonance imaging (MRI) hyperintensities in the limbic system [20].

The majority of reported HHV-6B encephalitis cases have occurred in recipients of unrelated HCT or HLA mismatched-related allogeneic HCT. Umbilical cord transplantation has also been identified as a risk factor for HHV-6B encephalitis [8,23,24]. In a study from the United States of 1344 allogeneic HCT recipients, the incidence of HHV-6B encephalitis was 1.4 percent overall (9.9 percent after cord blood transplantation and 0.7 percent after adult donor allogeneic HCT) [23]. Similarly, in a prospective study of 230 allogeneic HCT recipients in Japan, 7 patients (3.0 percent) developed HHV-6B encephalitis by day 70 following transplantation; encephalitis occurred more commonly in umbilical cord transplant recipients compared with recipients of other types of allografts (7.9 versus 1.2 percent) [8]. Haploidentical transplantation utilizing ex vivo graft manipulation and resulting in a graft composition that is rich in CD4+ T cells and poor in NK cells also appears to increase the risk of HHV-6B reactivation and encephalitis [25,26].

Delirium — In addition to the reports described above suggesting that HHV-6B can lead to encephalitis, several observational studies of HCT recipients have demonstrated associations between systemic HHV-6B reactivation and central nervous system dysfunction [2,5,10,11,27]. As an example, a study of 315 allogeneic HCT recipients demonstrated an independent association between HHV-6B reactivation and subsequent delirium, as indicated by neuropsychiatric screening [11]. HHV-6B reactivation was also independently associated with subsequent neurocognitive decline at approximately three months after HCT, as measured by baseline and follow-up neurocognitive testing. An important limitation of this study is that a CSF sample was obtained from only 4 of 19 patients with delirium, 2 of whom had HHV-6B deoxyribonucleic acid (DNA) detected by the polymerase chain reaction (PCR). In addition, brain MRI was obtained in only 9 of 19 patients with delirium; none had the typical abnormalities associated with HHV-6B encephalitis. Since MRI and CSF HHV-6B PCR were not obtained in all patients with delirium, it is not possible to determine how many of the patients with delirium had HHV-6B encephalitis. This study suggests that HHV-6B may lead to central nervous system dysfunction in the absence of encephalitis, but further studies are necessary to prove this.

Bone marrow suppression — Studies have suggested an association between HHV-6B reactivation and bone marrow suppression in HCT recipients [2,5,7,28-32]. In one study, in vitro assays demonstrated that HHV-6 inhibits granulocyte-macrophage and erythrocyte progenitors in human bone marrow [28]. In addition, HHV-6 has been shown to latently infect early bone marrow progenitors in vivo [33], and in vitro studies have demonstrated that HHV-6 infection of bone marrow progenitor cells suppresses the proliferation of granulocyte-macrophage, erythroid, and megakaryocyte cell lines [34,35].

Other possible associations — Other important clinical manifestations, such as acute GVHD [2,36-45] and cytomegalovirus reactivation [38,46,47], have been associated with HHV-6B reactivation. However, whether HHV-6B causes these entities (directly or indirectly) remains to be determined.

HHV-6B may cause pneumonitis in HCT recipients [7,48-50]. In a study of lung biopsy specimens from 15 HCT recipients with pneumonitis, high HHV-6B DNA levels in lung tissue were associated with idiopathic pneumonitis [48]. Higher HHV-6B DNA levels were also correlated with severity of GVHD. Another retrospective study tested for 28 pathogens in existing bronchoalveolar lavage (BAL) samples from 69 HCT recipients with idiopathic pneumonia syndrome and 21 asymptomatic HCT recipients [51]. HHV-6B was detected in 20 (29 percent) patients with idiopathic pneumonia syndrome and was the most frequent pathogen detected. In contrast, HHV-6B was only detected in one asymptomatic control (5 percent). A limitation of this study is that all BAL samples from controls were obtained at least 31 days after transplantation, whereas 70 percent of the cases with idiopathic pneumonia syndrome had their BAL performed prior to day 31. Another study of HCT recipients who underwent BAL found that subjects with HHV-6B detected in BAL fluid had significantly increased risk of overall mortality (adjusted hazard ratio [aHR] 2.18, 95% CI 1.41-3.39) and death from respiratory failure (aHR 2.50, 95% CI 1.56-4.01) compared with subjects whose BAL fluid tested negative for HHV-6B [52]. Furthermore, subjects with HHV-6B detected in BAL fluid who received antivirals within three days prior to BAL had an approximately 1 log10 lower median HHV-6B BAL fluid viral load, as well as a potential lower risk of overall mortality (aHR 0.42, 95% CI 0.16-1.10), compared with subjects with HHV-6B positive BAL fluid not receiving antivirals. In this study, intraparenchymal HHV-6 gene expression by ribonucleic acid (RNA) in situ hybridization was detected in the lung tissue in all three tested subjects with HHV-6B+ BALF and sufficient tissue RNA preservation. In some patients with pneumonitis, immunohistochemical staining of lung tissue showed HHV-6 antigens without any other identifiable pathogen [49]. However, the association of pneumonia with HHV-6B has been less certain in other reports because of the isolation of other potential pathogens such as cytomegalovirus, Pneumocystis jirovecii, and adenovirus [53,54]. The precise role of HHV-6B as a pulmonary pathogen requires additional investigation and further study is needed to confirm causality.

HHV-6B reactivation has been associated with an increased risk of mortality in HCT recipients [2,36,38,55]. However, it is not clear that the HHV-6B itself is the cause. In one study in which plasma samples were collected prospectively from 315 allogeneic HCT recipients and tested serially for HHV-6 DNA, HHV-6B reactivation (>1000 copies/mL) was associated with nonrelapse mortality (adjusted hazard ratio [aHR] 2.7, 95% CI 1.2-6.3) and subsequent acute GVHD (aHR 2.4, 95% CI 1.6-3.6) [38]. Similarly, in another study of clinical outcomes in 100 allogeneic HCT recipients, HHV-6B reactivation was associated with an increased risk of acute GVHD and all-cause mortality as well as a lower probability of monocyte engraftment (aHR 0.42, 95% CI 0.22-0.80) and platelet engraftment (aHR 0.47, 95% CI 0.21-1.1) [2].

Inherited chromosomally integrated HHV-6 — Inherited chromosomally integrated HHV-6 occurs when HHV-6A or HHV-6B integrates into germ-line cells, resulting in vertical transmission of chromosomally integrated HHV-6 [56,57]. Affected individuals have the HHV-6 genome integrated into a chromosome in every nucleated cell of their body, resulting in high levels of viral DNA in the blood and tissues in the absence of reactivation. Inherited chromosomally integrated HHV-6 is found in 1 to 2 percent of the population. Several studies in different settings have demonstrated the potential of the virus to reactivate from the integrated state [58-61]. However, the extent to which HCT recipients with integrated HHV-6 can also reactivate HHV-6 and suffer complications such as encephalitis is incompletely understood. At the very least, it may cause concern and confusion among clinicians when high viral levels are detected [62]. There is some evidence that it is associated with certain complications of HCT. In one study, grade 2 to 4 acute GVHD was significantly more frequent when HCT recipients or donors had integrated HHV-6 (aHRs 1.7-1.9) and CMV viremia was significantly more common among recipients with integrated HHV-6 (aHRs 1.7-3.1) [63]. In contrast, integrated HHV-6 status was not associated with an increased risk of chronic GVHD, delayed hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. A well-documented case of active HHV-6A infection in a patient with severe combined immunodeficiency illustrates the potential for integrated HHV-6 to reactivate and cause disease [64]. (See 'Detecting inherited chromosomal integration' below.)

TRANSMISSION — Most HHV-6B transmission events are thought to occur via shared saliva early in life. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection", section on 'Incubation period and transmission'.)

Congenital infection occurs in approximately 1 percent of births [65]. The majority of congenital infections have been attributed to germ-line inheritance of chromosomally integrated HHV-6 [57]. Inherited chromosomal integration occurs when HHV-6 is integrated into a germ cell of an individual; resulting offspring and subsequent generations have at least one copy of HHV-6 DNA in every cell of their body. Consequently, very high levels of HHV-6 DNA are detectable in blood and tissue samples of affected individuals.

PATHOGENESIS — As most individuals are infected with HHV-6B during early childhood, recipients of HCT have generally already been infected with HHV-6B prior to transplantation. Thus, following HCT, detectable virus in the plasma or serum is typically a result of reactivation of a latent infection.

Multiple cell types can support HHV-6 infection, including monocytes/macrophages [66,67] and cells of the central nervous system, including glial cells [68,69]. HHV-6 DNA has been detected in the cerebrospinal fluid of 42 percent of young children with evidence of acute or past HHV-6 infection [70] and in the brain tissue from approximately one-third of healthy or control individuals [71,72]. There is some evidence that HHV-6 invades the central nervous system through the olfactory pathway [73]. It is unclear whether HHV-6B isolated or detected in the setting of encephalitis originated from latent virus associated with monocytes in the blood, cells of the central nervous system, or both. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection", section on 'Cell tropism'.)

The pathogenesis of HHV-6 infection is discussed in greater detail separately. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection".)

HHV-6 ENCEPHALITIS — As noted above, HHV-6B encephalitis is the most clearly established clinical manifestation of HHV-6B reactivation in allogeneic HCT recipients and results in substantial morbidity [18-20,22,27,74].

Clinical manifestations — HHV-6B encephalitis has been described in several case reports and series [18-22,75,76]. This syndrome is characterized by confusion and anterograde amnesia with or without seizures, along with the detection of HHV-6B DNA in the cerebrospinal fluid (CSF) and/or evidence of active infection in brain tissue without other causes identified. The CSF cell count and protein concentration are usually normal or slightly elevated, and magnetic resonance imaging (MRI) typically demonstrates hyperintensities in the medial temporal lobes. Outcomes vary widely, with some patients recovering full neurologic function and others being left with residual neurologic deficits. (See 'Outcomes' below.)

Signs and symptoms — The symptoms and signs of HHV-6B encephalitis typically present between two and six weeks after transplantation. The range of findings is illustrated by the following case series:

In a series of nine patients, engraftment preceded the onset of the neurologic syndrome in all patients, and the median time to onset of neurologic symptoms was 29 days following HCT (range 14 to 61 days) [20]. The syndrome began as confusion in most patients and progressed to dense anterograde amnesia with patchy retrograde amnesia within several days in all patients. Fever was present in only two patients and could have been due to other processes that were present, such as graft-versus-host disease (GVHD) or concurrent infection.

In another series of nine patients, the median time from HCT to onset of symptoms was 21 days (range 6 to 145 days) [22]. All patients presented with confusion and headaches, but only two had fever. Common symptoms included personality changes, irritability, apathy, intermittent confusion, and forgetfulness. The neurologic examination in seven patients demonstrated anterograde amnesia, confusion, variable levels of disorientation, inability to follow complex commands, and bradyphrenia (slow thought process). The remaining two patients could not be evaluated because of intubation and/or sedation for another condition.

The seven patients who were initially alert and awake later became lethargic and somnolent. Four patients had clinical seizures and concomitant epileptiform activity on electroencephalogram (EEG) localizing to the temporal area. One patient developed wide variations in body temperature (between 30 and 38°C), fluctuations of blood pressure and heart rate, and central diabetes insipidus, suggesting hypothalamic involvement.

Overt seizures have been reported in 40 to 70 percent of patients [19,22,75], and seizures have been detected by electroencephalogram in an even higher proportion of patients, indicating that subclinical seizures occur [18,20,77]. Among patients with clinically apparent seizures, some have generalized seizures, whereas others have partial seizures [20].

Laboratory abnormalities — Among nine patients with HHV-6 encephalitis described above, hyponatremia due to inappropriate production of antidiuretic hormone (SIADH) occurred just prior to or with symptom onset in eight [20]. No other general laboratory abnormalities were observed.

Although HHV-6B DNA is detected in the blood of patients with HHV-6B encephalitis, it is not specific for HHV-6B encephalitis, since HHV-6 reactivation is common following HCT and only a small proportion of patients with HHV-6 reactivation develop encephalitis. (See 'Peripheral blood' below.)

Cerebrospinal fluid analysis — CSF findings are typically normal or only mildly abnormal in patients with HHV-6B encephalitis. The most common abnormalities are elevations in CSF white blood cell count and protein concentration. In a series of nine allogeneic HCT recipients with HHV-6B encephalitis, the median CSF white blood cell count was 5 leukocytes/mm3 (range 1 to 41) with lymphocyte predominance; the median protein concentration was 48 mg/dL (range 19 to 189) [20]. The glucose concentration was normal in all patients. Another case series showed similar findings [22].

Using the polymerase chain reaction (PCR), HHV-6B DNA levels from the CSF have varied widely in patients with HHV-6B encephalitis, with median values of approximately 15,000 to 30,000 copies/mL (range 600 to 1,000,000 copies/mL) [3,8,76]. (See 'Cerebrospinal fluid' below.)

Imaging findings — Abnormal findings are noted on brain MRI in most patients with HHV-6B encephalitis [19,75]. Acute abnormalities typically involve the medial temporal lobes, particularly the amygdala and hippocampus; hyperintensities in these regions are visualized on T2, fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences (image 1 and image 2 and image 3) [20,75,78]. Rarely, patients may have abnormalities in limbic structures outside the medial temporal lobes [79].

In a series of nine patients with HHV-6B encephalitis, serial MRIs after four weeks demonstrated the development of diffuse cerebral atrophy in seven of nine patients [22].

Computed tomography (CT) of the brain, especially when obtained early in the course of illness, is often normal [78].

EEG findings — As noted above, overt or subclinical seizures are common in patients with HHV-6B encephalitis (see 'Signs and symptoms' above). On electroencephalogram (EEG), focal abnormalities are often observed over the temporal or frontotemporal regions [20,22]. Abnormalities may include epileptiform activity, including electrographic seizures, periodic lateralized epileptiform discharges, and/or sporadic interictal discharges. Diffuse slowing can also occur.

Pathology — Autopsy studies of patients who died with HHV-6 encephalitis demonstrate lesions involving the white and/or gray matter and injuries characterized by necrosis, neuronal loss, demyelination, and astrogliosis [18,20,21,80,81]. Earlier in the course of infection, edema and inflammation may be seen [82]. Consistent with the clinical findings of memory impairment and focal findings on brain imaging, the hippocampus is the area most commonly involved on pathology [18,20,21,80,81], but other areas of the brain may also be involved [80,82].

Few published studies have attempted to correlate detection of HHV-6 with pathology. In the studies that have tried to do this, high levels of HHV-6 mRNA and HHV-6 antigen have been documented in diseased areas of the brain, with astrocytes being the predominant cell involved [21,80].

Differential diagnosis — Although HHV-6B is the most common cause of viral encephalitis in HCT recipients [83], a broad differential diagnosis, including other viral, bacterial, fungal, and parasitic pathogens, must be considered. Other herpesviruses, including Epstein-Barr virus, herpes simplex virus, varicella-zoster virus, and cytomegalovirus, may also cause viral encephalitis in the HCT setting, and CSF should be evaluated for these pathogens. JC virus, the cause of progressive multifocal leukoencephalopathy, is an uncommon cause of encephalitis in HCT recipients, but this diagnosis should be considered in patients with a consistent clinical picture. Other viral pathogens, such as arboviruses, enteroviruses, and certain respiratory viruses (influenza, adenovirus, metapneumovirus), should be pursued depending on the season and exposure history. (See "Viral encephalitis in adults" and "Acute viral encephalitis in children: Pathogenesis, epidemiology, and etiology" and "Herpes simplex virus type 1 encephalitis" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Epidemiology and pathogenesis of West Nile virus infection" and "Arthropod-borne encephalitides" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Human metapneumovirus infections".)

Bacterial infections and fungal pathogens, such as Aspergillus, may disseminate to the brain and present with encephalopathy or seizures. Lung and brain imaging, along with microbiology studies of the CSF and blood, can assist in the identification of these infections. Although relatively rare, tuberculosis and parasitic infections, such as toxoplasmosis, should be considered, depending on whether the patient comes from an endemic region, whether there is a history of untreated latent tuberculosis, whether the pretransplant Toxoplasma serology was positive, and whether the patient has been receiving prophylactic drugs with activity against Toxoplasma (eg, trimethoprim-sulfamethoxazole). (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Central nervous system infection' and "Central nervous system tuberculosis: An overview" and "Toxoplasmosis in patients with HIV", section on 'Toxoplasmic encephalitis'.)

Noninfectious etiologies should also be considered in allogeneic HCT recipients with altered mental status, since a wide range of causes can contribute to altered mental status in such patients. Examples include electrolyte abnormalities and adverse effects from narcotics or benzodiazepines. Reversible posterior leukoencephalopathy syndrome, which is characterized by headaches, altered consciousness, visual disturbances, and seizures, can occur as a toxicity of calcineurin inhibitors; this diagnosis should be considered in patients with suggestive findings since calcineurin inhibitors are used in allogeneic HCT recipients to prevent GVHD. (See "Reversible posterior leukoencephalopathy syndrome", section on 'Immunosuppressive therapy'.)

Diagnosis

Clinical suspicion and diagnostic approach — HHV-6 encephalitis should be suspected in HCT recipients with compatible neurologic findings, particularly confusion, anterograde amnesia, and/or seizures. While these findings can be subtle, onset is typically acute and occurs two to six weeks following transplantation.

Because progression can be rapid and HHV-6 encephalitis can be fatal, we generally start treatment when suspicion is raised. Concurrently, we pursue the following diagnostic evaluation:

MRI of the brain

Lumbar puncture with CSF analysis, including HHV-6 PCR

Quantitative PCR for HHV-6 DNA from whole blood or plasma

The detection of HHV-6 DNA in the CSF confirms that diagnosis in an HCT recipient with characteristic findings and the absence of other causes. Features that further corroborate the diagnosis include medial temporal lobe involvement on brain MRI and the detection of HHV-6 DNA in blood or plasma. While not strict, the height of the viral load in either blood or CSF correlate with the likelihood of encephalitis [3,5,8,9,76].  

In some cases, HHV-6 may be detected in blood or plasma through routine post-transplant screening. In such cases, we perform a careful neurologic examination and often an MRI and lumbar puncture. These cases are particularly challenging because HHV-6 can reactivate in the setting of immunosuppression without causing encephalitis or other syndromes.  

Notably, chromosomal integration of HHV-6 can cause a false-positive HHV-6 PCR result in patients without evidence of encephalitis or other signs or symptoms attributable to HHV-6 disease. (See 'Antiviral selection' below.)

If other causes of encephalitis are suspected, studies for other specific pathogens should be obtained (eg, herpes simplex virus PCR; varicella-zoster virus PCR; during the summer and fall, mosquito-borne viruses that cause encephalitis). (See 'Polymerase chain reaction' below and 'Imaging findings' above and 'Differential diagnosis' above and "Viral encephalitis in adults", section on 'Diagnosis'.)

Diagnostic tests for HHV-6 — Approaches to identifying HHV-6 include direct detection of the virus (by PCR, antigenemia assays, or culture) and detection of an immunologic response to the virus (by serology). Because serology is often negative in HCT recipients, direct detection of the virus is preferred. Detection of viral nucleic acids in blood is the most frequently used approach to detect HHV-6 in the clinical setting (table 1). Similarly, detection of HHV-6 by PCR from the CSF is the preferred method for detection in patients with HHV-6B encephalitis.

Although isolation of HHV-6 from the blood by culture is considered the gold standard indicator of viremia, culturing the virus is labor intensive and requires a relatively long turn-around time. Thus, it is not widely available and is rarely used outside research settings.

Polymerase chain reaction — PCR can be performed on CSF, peripheral-blood samples (plasma, serum, or whole blood), or tissue. Detection of viral nucleic acids by PCR may reflect active or latent infection, depending on the clinical setting and the specimen tested. For instance, detection of viral DNA in noncellular samples is generally thought to reflect active viral replication, whereas detection of viral DNA in cellular samples may represent either active replication or latent infection.

Quantitative PCR methods are helpful for determining how high the HHV-6 DNA level is. However, PCR testing has not been standardized and it has, therefore, not been possible to develop cut-offs that are reliably predictive of disease, although evidence linking higher viral loads in the blood with encephalitis is accumulating (see 'Peripheral blood' below). We prefer to use a quantitative PCR assay so that the viral load can be determined. This can be helpful for determining trends over time. Real-time PCR can also be used to distinguish between HHV-6 species [84,85].

Droplet digital PCR is an approach that provides precise quantification of the ratio of HHV-6 to cellular DNA [86]. The assay can be useful when trying to identify chromosomally integrated HHV-6. (See 'Detecting inherited chromosomal integration' below.)

Reverse-transcription PCR detects messenger RNA and, thus, indicates actively replicating virus [87]. This can be helpful, especially when dealing with cellular specimens (eg, whole-blood or peripheral-blood mononuclear cells). Reverse-transcription PCR is not widely available, and few studies have been performed in order to determine the sensitivity and specificity of viral RNA detection and its association with disease.

Cerebrospinal fluid — In the absence of another identified etiology for acute encephalopathy, detection of HHV-6 in the CSF is considered diagnostic of HHV-6B encephalitis. Most but not all patients diagnosed with HHV-6B encephalitis have a positive HHV-6 PCR of the CSF at presentation [20]. As noted above, the HHV-6 viral load from the CSF varies widely in patients with HHV-6 encephalitis, with median values of approximately 15,000 to 30,000 copies/mL (range 600 to 1,000,000 copies/mL) [3,8,76].

Many young children have detectable HHV-6B in their CSF around the age when primary HHV-6B infection occurs [88]. It is unknown what proportion of HCT recipients has detectable HHV-6B in the CSF at the time of HHV-6B reactivation, since reactivation occurs early after transplantation, a time when many HCT recipients have not yet engrafted and their physicians are reluctant to perform lumbar punctures. Limited evidence suggests that HHV-6B is rarely detected in the CSF of immunocompromised patients without encephalitis [82]. In one study, HHV-6 DNA was detected in CSF specimens from 5 of 22 HCT recipients with central nervous system (CNS) symptoms (23 percent) and in 1 of 107 immunocompromised controls without CNS symptoms (0.9 percent); however, most of the controls were not HCT recipients [82]. In another study, HHV-6 was detected in 0 of 29 CSF samples from HCT recipients without encephalitis; CSF samples were obtained a median of 51 days after HCT, a slightly later time point than is typical with HHV-6 encephalitis [20]. In contrast with these studies, a retrospective study of HHV-6 detection in CSF samples from HCT recipients demonstrated that not all cases of HHV-6 detection in CSF reflect HHV-6 encephalitis [89]. In this study, of the 51 HCT recipients with HHV-6 detected in the CSF, 37 met criteria for HHV-6 CNS dysfunction. The remaining 14 patients included 8 patients who had an alternative explanation for their symptoms and 6 patients who did not have neurologic symptoms or who had spontaneous resolution of their symptoms. These six patients were not treated for HHV-6B and had no morbidity attributable to HHV-6.

In a study of 11 HCT recipients with HHV-6 detected by PCR in the CSF and serum (8 of whom had HHV-6 encephalitis) who were treated with foscarnet and/or ganciclovir, the concentration of HHV-6 in the CSF declined more slowly than in the serum [76]. Furthermore, it has been demonstrated in three patients who died with or after HHV-6 encephalitis that active HHV-6 infection can still be detected in the brain tissue even after HHV-6 DNA has become undetectable in the serum and CSF [21]. This suggests that resolution of CSF HHV-6 DNA alone should not be used to shorten therapeutic courses for HHV-6 encephalitis.

Peripheral blood — Detection of HHV-6B DNA in plasma or serum correlates well with viremia and seroconversion [90,91]. HHV-6B DNA detection in whole blood has also been used to identify HHV-6 reactivation [92], with similar frequencies of detection after HCT as seen in studies using plasma or serum. In contrast, detection of viral DNA in peripheral-blood mononuclear cells by PCR can be difficult to interpret since the mononuclear cell is a site of virus latency.

Although peripheral-blood HHV-6B PCR can be helpful for establishing that HHV-6 reactivation has occurred, it is not specific for HHV-6B encephalitis, since HHV-6 reactivation is common following HCT and only a few patients with HHV-6 reactivation develop encephalitis (see 'Epidemiology' above). However, a higher concentration of HHV-6B DNA in peripheral-blood leukocytes or plasma after HCT has been observed in patients with encephalitis compared with patients without encephalitis [5,9]. In a prospective study of 230 allogeneic HCT recipients in whom plasma HHV-6B DNA load was measured twice weekly until day 70 following HCT, 7 of 86 patients (8.1 percent) with high-level HHV-6B replication (plasma HHV-6 DNA ≥104 copies/mL) developed HHV-6B encephalitis compared with none of 144 patients without high-level HHV-6B replication [8]. In each of the seven patients with HHV-6B encephalitis, CNS symptoms and signs developed concomitant with the peak plasma HHV-6B DNA value (range 21,656 to 433,639 copies/mL). The median time between the first detection of HHV-6B DNA in the plasma and development of CNS dysfunction was 4 days (range 1 to 14 days). In another study in which HHV-6B PCR was performed on the plasma of 110 allogeneic HCT recipients, a higher level of HHV-6B DNA (greater than the median value of 138 copies/mL) was associated with subsequent CNS dysfunction [2]. Based on these data, patients with high levels of HHV-6B DNA from the peripheral blood appear to be at greater risk for CNS dysfunction and HHV-6B encephalitis.

As noted above, in a study of 11 HCT recipients with HHV-6 detected by PCR in the CSF and serum (8 of whom had encephalitis) who were treated with foscarnet and/or ganciclovir, the levels of HHV-6 DNA in the serum became undetectable more quickly than in the CSF [76]. Therefore, it is not adequate to rely on HHV-6 testing of the peripheral blood alone in an HCT recipient with signs and symptoms of encephalitis.

Inherited chromosomal integration of HHV-6 in the donor's cells or the recipient's cells can cause high concentrations of HHV-6 in the blood or CSF by PCR in the absence of active infection. This is discussed in greater detail below. (See 'Detecting inherited chromosomal integration' below.)

Antigenemia assays — Direct detection methodologies using antigenemia have been described [32,93]. In contrast with PCR testing of plasma or serum specimens, approximately 60 percent of HCT patients will have positive tests for antigenemia prior to HCT. Following HCT, the proportion of patients with HHV-6B antigenemia increases to approximately 75 percent overall and is as high as 90 percent in recipients of allogeneic transplants from unrelated donors [32,93].

Serology — Serologic methods have many limitations, including the low sensitivity of antibody assays in severely immunocompromised patients. There are serologic approaches that incorporate antibody avidity, exploiting the fact that, during primary infection, the first immunoglobulin (Ig)G antibodies have low avidity but, with time and maturation of the immune response, higher avidity antibodies are produced [94]. This allows the immune response to primary infection to be distinguished from either maternal antibodies or antibodies of established infection. Although this may prove helpful in certain settings, primary HHV-6 infection is a concern for only a small fraction of HCT recipients, since most patients have been infected with HHV-6 prior to transplantation.

Detecting inherited chromosomal integration — Inherited chromosomally integrated HHV-6 can cause a confusing clinical picture in the setting of HCT. (See 'Inherited chromosomally integrated HHV-6' above.)

Population-based studies have estimated germ-line inheritance of HHV-6 to occur in about 1 percent of the population [95,96]. Thus, a small proportion of HCT donors and recipients will have inherited chromosomal integration. Because patients with inherited HHV-6 have at least one copy of the viral genome in each cell of their body, they have unusually high levels of HHV-6 DNA in blood, CSF, and tissues. Both HHV-6A and HHV-6B can be integrated and inherited. Since the vast majority, if not all, of reactivation events following HCT are due to HHV-6B, detection of HHV-6A can be a clue to chromosomally integrated HHV-6 [2-4].

When the donor has inherited HHV-6, HHV-6 levels will increase in the recipient with engraftment and very high levels are often detected, particularly when whole blood is tested (figure 1) [62,97]. As an example, in one HCT recipient who received a transplant from a donor with chromosomal integration, persistent HHV-6 concentrations of 2.5 x106 to 10 x106 copies/mL were detected in whole blood following engraftment [62]. In another report, two HCT recipients who received transplants from donors with chromosomal integration had 6.1 x 106 and 9.7 x 105 copies/mL in the whole blood following engraftment, but only 3600 and 15,400 copies/mL in the plasma, respectively [97]. Other features of chromosomal integration in donor cells are that HHV-6 DNA levels remain persistently and stably elevated and do not decline with time or antiviral therapy [98]. Consequently, serial testing and quantification of HHV-6 DNA copies per cell assayed can provide evidence of inherited HHV-6 if approximately one copy of HHV-6 per cell assayed is consistently detected over time.

In contrast with the pattern observed when the HCT recipient receives a transplant from a donor with chromosomal integration with HHV-6, when the HCT recipient has inherited HHV-6, high levels of HHV-6 DNA can be detected in the blood immediately after transplantation, which then decrease with successful engraftment (figure 2) [99].

As noted above, high levels of HHV-6 DNA can also be detected in the CSF in individuals with chromosomal integration. As an example, among 21 patients with presumed chromosomal integration, HHV-6 DNA was detected in the CSF with a mean level of 4.0 log10 copies/mL (95% CI 3.5-4.5) [100]. This was higher than the mean level detected in immunocompetent children with primary HHV-6 infection (2.4 log10 copies/mL, 95% CI 1.0-3.7), but similar to levels detected in HCT recipients with HHV-6 encephalitis.

Distinguishing inherited HHV-6 from HHV-6-associated disease can be challenging, especially when dealing with a single positive result. Fluorescence in situ hybridization (FISH) with a specific HHV-6 probe performed on metaphase chromosome preparations from peripheral blood will demonstrate integrated HHV-6 [62,101,102]. In addition, in contrast with individuals with latent HHV-6 infection, individuals with integrated HHV-6 have detectable HHV-6 in their hair follicles [103]. Thus, if FISH is not available, PCR testing of hair follicles for HHV-6 DNA can be performed to identify an individual with integrated HHV-6. This would mean testing the donor's hair follicles in the case of an HCT recipient whose donor is suspected to have integrated HHV-6. When there is concern for integrated HHV-6 in the HCT donor cells, testing of donor serum or whole blood with HHV-6 PCR may provide supporting evidence for integrated HHV-6 [97,103]. A third option is use of droplet digital PCR, an approach that provides precise quantitation of the ratio of HHV-6 to cellular DNA [86]. With this assay, inherited chromosomally integrated HHV-6 is accurately identified when cellular samples (eg, whole blood, buffy coat) are used, and the assay gives a ratio very close to 1 of HHV-6/cell. This assay can also be used to identify reactivation of HHV-6B in a patient with chromosomally integrated HHV-6A [104].

The possibility of inherited chromosomally integrated HHV-6 should be considered in the setting of high and persistent levels of HHV-6 DNA in the peripheral blood, particularly if the patient has no clinical signs of encephalitis and/or the level of viremia does not decline following initiation of antiviral therapy with activity against HHV-6. It appears that HHV-6-related disease should not necessarily be ruled out on the basis of identifying chromosomally integrated HHV-6. Further research is needed to determine optimal methods for identifying active HHV-6 infection in the setting of chromosomally integrated HHV-6.

Treatment — The treatment of encephalitis caused by HHV-6B involves antiviral therapy and, when seizures are present, anticonvulsant therapy. We do not recommend treatment of HHV-6B viremia in the absence of HHV-6B encephalitis or another clinical entity that can be attributed to HHV-6B. (See 'Antiviral prophylaxis and pre-emptive therapy' below.)

Antiviral selection — Although the optimal therapy is unknown, based on available data, we recommend foscarnet or ganciclovir for the treatment of HHV-6B encephalitis in HCT recipients [105-107]. Cidofovir has been proposed as a second-line agent, but it is avoided as a first-line agent because it is highly nephrotoxic [107]. The dosing of the first-line agents in patients with normal renal function is as follows:

Foscarnet – 60 mg/kg intravenously (IV) every 8 hours or 90 mg/kg IV every 12 hours

Ganciclovir – 5 mg/kg IV every 12 hours

For patients who have not improved or who have worsened on monotherapy, we sometimes switch from the agent that the patient has been receiving to the other agent (eg, foscarnet to ganciclovir or vice versa). It is important to note that cross-resistance has been reported for cytomegalovirus due to polymerase gene mutations, particularly when switching from foscarnet to ganciclovir or cidofovir [108]; it is possible that HHV-6B could harbor the same mutations. Unfortunately, resistance testing for HHV-6B is not available. We occasionally use combination therapy with full doses of foscarnet and ganciclovir in very severe cases or when there is lack of clinical improvement or worsening on single-agent therapy.

Neither foscarnet nor ganciclovir has been approved by the US Food and Drug Administration for the treatment of HHV-6B infection. However, in vitro studies demonstrate that foscarnet, ganciclovir, and cidofovir have activity against HHV-6B [109]. Observational data suggest foscarnet, ganciclovir, and brincidofovir (a lipid conjugate of cidofovir) have activity against HHV-6B in vivo [76,110]. Studies of patients with HHV-6B encephalitis suggest an association between foscarnet or ganciclovir treatment and a reduction of viral DNA levels in serum and CSF, but these studies lacked control groups [76]. In one post hoc analysis of a randomized trial evaluating >150 allogeneic HCT recipients, brincidofovir use was associated with reduce incidence of HHV-6B viremia when compared with placebo [110].

In a retrospective observational study that included 145 allogeneic HCT recipients with HHV-6B encephalitis, full-dose foscarnet or full-dose ganciclovir were associated with better neurologic response rates compared with lower-dose therapy (for foscarnet: 93 versus 74 percent; for ganciclovir: 84 versus 58 percent) [24]. The rate of sequelae or death due to HHV-6B encephalitis was not significantly different in those who received foscarnet compared with those who received ganciclovir; however, the rate of death from any cause within 30 days after the development of HHV-6 encephalitis was lower in patients who received foscarnet. Given the observational design of the study and the potential of unmeasured confounding factors, further research is needed to determine if one antiviral is superior.

Important toxicities — Both foscarnet and ganciclovir are associated with important toxicities. Foscarnet is associated with electrolyte depletion, which can lower the seizure threshold, as well as nephrotoxicity. It has occasionally been associated with genital ulcers. When foscarnet is used, electrolytes should be monitored frequently (eg, at least once daily) and repleted aggressively. We also recommend prehydration (eg, 500 cc normal saline) before each dose of foscarnet to protect the kidneys. (See "Foscarnet: An overview", section on 'Electrolyte abnormalities' and "Foscarnet: An overview", section on 'Genital ulcerations'.)

Ganciclovir can cause bone marrow suppression, which is a particular concern in HCT recipients. (See "Ganciclovir and valganciclovir: An overview", section on 'Toxicity'.)

Cidofovir is not used as a first-line agent because it is highly nephrotoxic [107].

Duration and monitoring during therapy — No published studies have evaluated the optimal duration of therapy for HHV-6B encephalitis. Although not based on comparative clinical trial data, we recommend giving antiviral therapy for 21 days for most patients with HHV-6B encephalitis, particularly those who have had a good clinical response to therapy. We treat patients who have had a poor clinical response and/or in whom the CSF or peripheral-blood HHV-6B remains detectable for a longer period (up to six weeks). In patients who require a longer duration of antiviral therapy but who are experiencing toxicity, the class of antiviral agent can be changed (from foscarnet to ganciclovir or vice versa) with the caveat noted above. (See 'Antiviral selection' above.)

We recheck the HHV-6B viral load from the peripheral blood weekly during therapy until it has become undetectable. We recheck the CSF HHV-6B viral load in patients who have not improved or who have worsened clinically despite appropriate antiviral therapy. Although the expected response of the CSF HHV-6B viral load to antiviral therapy has not been clearly established, we treat patients who continue to have substantial neurologic deficits and who have not had a significant reduction in CSF HHV-6B levels for a longer period than patients who have both improved clinically and who have had a substantial reduction in the CSF HHV-6B viral load.

Optimally, we continue antiviral therapy until the peripheral-blood HHV-6B PCR is undetectable (and for no fewer than 21 days). If there is an indication for rechecking the CSF HHV-6B viral load, then we continue antiviral therapy until it is undetectable as well. However, in the absence of clear improvement over an extended period (based on clinical response and/or PCR results), prolonged treatment is unlikely to provide further benefit and may be toxic. One possible reason for a lack of virologic response is antiviral drug resistance (see 'Antiviral selection' above). Thus, the potential risks and benefits of the antiviral regimen should be assessed when a prolonged course is considered.

Active HHV-6B infection can sometimes still be detected in brain tissue even after HHV-6B DNA has become undetectable in the serum and CSF [21]. This suggests that a reduction in peripheral-blood or CSF HHV-6B viral load to undetectable levels should not be used to shorten the therapeutic course for HHV-6B encephalitis to less than 21 days.

Seizure prevention and treatment — Given the substantial incidence of overt or subclinical seizures in patients with HHV-6B encephalitis, we have a low threshold for checking an EEG in patients with subtle signs that may be consistent with seizure activity, including a reduced level of consciousness that does not have another explanation. In patients with overt seizures, it is not necessary to obtain an EEG.

In patients with clinical or EEG evidence of seizure activity, we recommend an anticonvulsant that will not interact with other agents that the patient is taking (eg, for GVHD or antifungal prophylaxis or treatment). We favor levetiracetam in such patients since it does not affect cytochrome P450. (See "Initial treatment of epilepsy in adults", section on 'Efficacy' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Levetiracetam'.)

Electrolyte depletion associated with foscarnet can increase the risk of seizures. In patients receiving foscarnet, electrolytes should be monitored closely and repleted aggressively. (See "Foscarnet: An overview", section on 'Electrolyte abnormalities'.)

Antiviral prophylaxis and pre-emptive therapy — Although small studies exploring the safety of pre-emptive or prophylactic antiviral therapy directed against HHV-6B in HCT patients have been conducted, large studies demonstrating the efficacy and safety of HHV-6B prophylaxis or pre-emptive therapy have not been performed. Therefore, there are insufficient data to recommend prophylactic antiviral strategies or pre-emptive monitoring and treatment aimed at reducing the risk of HHV-6B-associated disease, such as HHV-6B encephalitis [106].

Studies of recipients of solid organ transplants who received cytomegalovirus-directed prophylactic ganciclovir suggest a possible effect on HHV-6B [111,112]. Although ganciclovir prophylaxis was not associated with a decreased frequency of HHV-6 reactivation in a study of 134 renal transplant recipients, it was associated with delayed onset and shortened duration of HHV-6 detection [112]. Similarly, several small retrospective studies in HCT recipients suggest a potential benefit of prophylactic ganciclovir in reducing HHV-6B activity and its associated manifestations [113-115].

In a small retrospective study in which 118 unrelated bone marrow or umbilical cord HCT recipients received low-dose foscarnet prophylaxis (50 mg/kg IV per day) or no prophylaxis for 10 days following engraftment, no significant reduction of high-level HHV-6 reactivation (plasma DNA ≥104 copies/mL) was seen in those who received prophylaxis compared with those who did not (19.4 versus 33.8 percent) [116]. HHV-6 encephalitis occurred in three patients who received foscarnet prophylaxis, and the incidence of HHV-6 encephalitis did not differ significantly between those who received prophylaxis and those who did not (4.5 versus 9.9 percent). It is possible that the dose of foscarnet was too low to prevent HHV-6B reactivation and encephalitis. It is also possible that a larger study would have been able to show a statistically significant difference between the groups.

A prospective multicenter trial evaluated the effects of prophylactic foscarnet given from days 7 to 27 following transplantation on the occurrence of HHV-6B reactivation, encephalitis, and acute GVHD in 57 umbilical cord blood transplant recipients compared with a historical control group [117]. Although foscarnet significantly suppressed systemic HHV-6 reactivation, it failed to prevent the development of HHV-6 encephalitis at 60 days post-transplant. Suppression of HHV-6 reactivation by foscarnet did not show any reduction in the incidence of acute GVHD.

Two very small (six to eight patients receiving drug) prospective studies have explored pre-emptive foscarnet therapy in HCT recipients [118,119]. These studies highlight the challenge of initiating pre-emptive therapy after a viral threshold has been reached but prior to the onset of manifestations of HHV-6B disease in high-risk patients.

Outcomes — Outcomes of HHV-6B encephalitis have been difficult to evaluate since allogeneic HCT recipients often have complex comorbidities. It appears that outcomes vary widely, with some patients recovering full neurologic function and other patients being left with residual neurologic deficits. Similarly, some patients with HHV-6B encephalitis have appeared to die from encephalitis, but many have died of other identifiable causes [18,20,21,80,81].

In a review of case reports and case series of patients with HHV-6B encephalitis, information was provided on the neurologic course and outcomes in 44 cases [19]. Although difficult to determine with certainty, 11 patients (25 percent) had a progressive course and died within one to four weeks of diagnosis. Eight patients (18 percent) improved but were left with residual neurologic compromise. Nineteen patients (43 percent) made a full recovery, although, for some, the recovery process lasted several weeks and required rehabilitation services. Six patients (14 percent) initially showed improvement but then succumbed to respiratory failure, multiorgan failure, or other documented infections. Whether these conditions were directly or indirectly a result of the HHV-6 infection remains unclear. Similar observations were made in a surveillance study of HHV-6B encephalitis in HCT recipients in Japan [75].

In a series of nine patients, two patients developed relapse or a second episode of encephalitis two to three months after treatment of the initial episode [22].

There are few studies of the long-term neurocognitive outcomes associated with HHV-6B encephalitis. In a retrospective study of patients with HHV-6B encephalitis who were followed for a median of 1651 days following development of encephalitis, 121 were evaluated for CNS dysfunction after completing antiviral therapy [24]. Of these, 69 (57 percent) were found to have persistent neuropsychologic dysfunction. The most common sequela was memory impairment (in 33 percent).

MANAGEMENT OF OTHER ENTITIES POTENTIALLY ASSOCIATED WITH HHV-6B — Recommendations do not exist for the treatment of clinical entities other than encephalitis that may be associated with HHV-6B reactivation, such as pneumonitis or bone marrow suppression/delayed engraftment. Some experts would consider giving foscarnet or ganciclovir to HCT recipients with lower respiratory tract disease and HHV-6B detection in BAL fluid, especially if the viral load is relatively high and a more likely explanation for the pulmonary findings is not apparent [52]. Some experts also consider treating HHV-6B when detected in plasma or serum in HCT recipients with a clinical entity potentially associated with HHV-6B when other etiologies with established causality have been ruled out.

SUMMARY AND RECOMMENDATIONS

Prevalence of HHV-6 reactivation – Human herpesvirus 6B (HHV-6B) reactivation occurs in 30 to 50 percent of allogeneic hematopoietic cell transplantation (HCT) recipients, and viremia is typically detected two to four weeks after HCT. (See 'Epidemiology' above.)

Characteristics of HHV-6 encephalitis – A small subset of allogeneic HCT recipients with HHV-6B reactivation develops HHV-6 encephalitis, characterized by confusion and short-term memory loss and/or anterograde amnesia with or without seizures. In such patients, HHV-6B DNA is usually detected in the cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) often shows hyperintensities in the medial temporal lobes. (See 'Epidemiology' above and 'Clinical manifestations' above.)

Diagnosis of HHV-6 encephalitis – We recommend that HCT recipients who develop signs of encephalitis, especially during the first several weeks after transplantation, undergo lumbar puncture to have their CSF tested for HHV-6 using quantitative polymerase chain reaction (PCR) as well as for routine CSF studies and for other possible infectious agents. Such patients should also have peripheral blood (eg, plasma) tested using quantitative HHV-6 PCR and should undergo MRI to look for evidence of limbic encephalitis (image 1 and image 2 and image 3). The diagnosis of HHV-6B encephalitis is established in allogeneic HCT recipients with the characteristic clinical findings in whom HHV-6 DNA is detected in the CSF without other causes identified. (See 'Clinical suspicion and diagnostic approach' above.)

Chromosomal integration – The possibility of chromosomally integrated or inherited HHV-6 should be considered in the setting of extremely high and persistent levels of HHV-6 DNA in the peripheral blood, particularly if the patient has no clinical signs of HHV-6 encephalitis (figure 1). (See 'Detecting inherited chromosomal integration' above.)

Treatment of HHV-6 encephalitis – All patients with HHV-6B encephalitis should receive an antiviral agent with activity against HHV-6B. We recommend that such patients be treated with foscarnet or ganciclovir (Grade 1C). We give antiviral therapy for 21 days for most patients with HHV-6 encephalitis, particularly those who have had a good clinical response to therapy. Patients who have had a poor clinical response and/or in whom the CSF or peripheral-blood HHV-6 remains detectable should be treated for a longer period. In patients who require a longer duration of antiviral therapy but who are experiencing toxicity, the class of antiviral agent can be changed. (See 'Treatment' above.)

Toxicities associated with treatment – Important toxicities of foscarnet include nephrotoxicity and electrolyte depletion; prehydration and close monitoring of electrolytes are warranted when foscarnet is given. An important toxicity of ganciclovir is bone marrow suppression. (See 'Treatment' above.)

Viral load monitoring on therapy – We recheck the HHV-6 viral load from the peripheral blood weekly during therapy until it has become undetectable. We recheck the CSF HHV-6 viral load in patients who have not improved or who have worsened clinically despite appropriate antiviral therapy. (See 'Duration and monitoring during therapy' above.)

Evaluation for seizure – Patients with HHV-6B encephalitis who have subtle signs that are suggestive of seizure activity should undergo an electroencephalogram (EEG). In patients with clinical or EEG evidence of seizure activity, we use levetiracetam. (See 'Seizure prevention and treatment' above.)

No clear preventive therapy – There are insufficient data to recommend prophylactic or pre-emptive therapy of HHV-6 viremia in HCT recipients in an attempt to prevent the development of encephalitis. (See 'Antiviral prophylaxis and pre-emptive therapy' above.)

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Topic 16146 Version 32.0

References

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