Human Herpesvirus 6 in Transplant Recipients
Authors: Danielle M Zerr, Raymund R Razonable
Virology
HHV-6 is a member of the Roseolovirus genus of the β-herpesvirus subfamily of human herpesviruses. There are two subtypes of HHV-6: type A and type B. The two subtypes share certain biological properties and a high level of sequence homology, but are clearly distinct, both virologically and epidemiologically. HHV-6 infects multiple cell lines and tissues and establishes latent infection in mononuclear cells. HHV-6 DNA and gene transcription has been detected in normal brain tissue (4, 33) and HHV-6 DNA is found in the CSF with a high frequency (42%) in children with acute or past HHV-6 infection (2). In less than 1% of the individuals, HHV-6 persistence occurs as a result of the integration of the virus into the host chromosome and passage through the germ line (27, 48).
Epidemiology
HHV-6 infects virtually all children within the first few years of life and like other herpesviruses, it establishes latency after primary infection. After transplantation, HHV-6 may exit the latent state and actively replicate. This active HHV-6 infection is estimated to occur in 20 to 50% of transplant recipients (18, 20, 54, 57). The estimates vary, presumably due to the populations and diagnostic methods studied, but have been relatively consistent (approximately 40% in studies of HSCT recipients) especially when PCR of plasma or serum is used. HHV-6 reactivation occurs relatively early, generally within the first 2-4 weeks after transplantation (20, 54, 57). Risk of HHV-6 end organ disease has been harder to quantify but is considered to be lower than the risk of reactivation of the virus as discussed further, below (Clinical Manifestations). Type B virus accounts for the vast majority of the documented primary infections in children as well as reactivation events in patients receiving transplants. The epidemiology of HHV-6A is less clear.
Risk factors for HHV-6 infections are not completely defined. Given the high seroprevalence, most infections after organ transplantation likely represent reactivation of latent viruses, especially in adults. It is therefore reasonable to assume that the intensity of pharmacologic immunosuppression may be a risk factor, potentially through prolonged suppression of memory responses. Certain specific agents, including muromunab-CD3 (OKT3), an investigational anti-CD3 monoclonal antibody (BC3), and alemtuzumab have been associated with active HHV-6 infection after transplantation (23, 34, 55). In the setting of HSCT, younger age, underlying disease, receipt of glucocorticoids, receipt of unrelated transplant, and receipt of cord blood transplant are identified risk factors for HHV-6 reactivation and HHV-6 end organ disease (17, 28, 43, 54, 57).
Pathogenesis
Latent virus serves as the reservoir for endogenous viral reactivation after transplantation or as potential vectors of transmission to susceptible individuals via the transplanted organ itself. Given the high (90-95%) seroprevalence of HHV-6 in adults, most active infections after transplantation are thought to originate from reactivation of endogenous latent virus. Pediatric transplant recipients under 2 years of age, however, may be HHV-6 seronegative prior to transplantation and therefore may acquire HHV-6 from the transplanted organ (11). Primary infections, presumably of donor origin, may occur in seronegative transplant recipients, and a few patients have developed fatal primary HHV-6 infections (40, 42).
Clinical Manifestations
HHV-6 associated sequelae may be viewed as either direct effects of the infection or from the consequences of virus-induced immune modulation. Most cases of HHV-6 active infection and disease after transplantation have been due to HHV-6B, although a few cases of HHV-6A associated disease have been reported35.
Overt disease directly due to HHV-6 has been estimated to occur in less than 1% of patients receiving solid organ transplantation (3, 20). In this setting, HHV-6 disease may manifest as a febrile syndrome accompanied by some degree of bone marrow suppression, an illness similar to CMV syndrome (38). In some cases, HHV-6 has been detected in the blood of patients with clinical syndromes attributable to CMV disease (15, 16, 38). To what extent HHV-6 may be directly causing or contributing to the clinical symptoms in these patients is not clear. HHV6 has also been reported as a cause of febrile dermatosis (46), hepatitis (35), gastroduodenitis (36), colitis (7, 24), pneumonitis (31), and encephalitis (31, 44) after solid organ transplantation. HHV-6 reactivation (usually defined by detection of viral nucleic acids in serum or plasma or whole blood) in HSCT has been associated with subsequent bone marrow suppression, GVHD, and encephalitis (17, 28, 57).
HHV-6-associated hepatitis, colitis, and pneumonitis have also been described in HSCT recipients, mainly as case reports and case series. HHV-6 encephalitis deserves special mention due to the relative strength and quantity of data which support a causal association and the potential severity of the condition. HHV-6 encephalitis as an entity has been defined through prospective surveillance studies and a number of case reports and case series (58). Encephalitis typically occurs within 4-6 weeks after transplantation and is characterized by confusion, loss of short term memory, and seizures. Patients will often have normal CSF profiles; elevated protein is the most common abnormality. Brain imaging is often abnormal with hallmark abnormalities found in the medial temporal lobes. Approximately a quarter of patients with HHV-6 encephalitis appear to die of their infection while a high proportion of the survivors experience long-term morbidity.
HHV-6 may cause important indirect effects, possibly as a result of the immunomodulatory effects of active viral infection. In this vein, HHV-6 has been associated with CMV disease (9, 20), (30), fungal and other opportunistic infections (10, 41), early fibrosis due to hepatitis C virus recurrence after liver transplantation (21, 47), bronchiolitis obliterans following lung transplantation (32, 42), graft versus host disease after HSCT (57), and a higher mortality rate after liver (41), heart-lung (22), and HSCT transplantation (57). There are conflicting data on the association between HHV-6 infections with allograft rejection and dysfunction (14, 20, 25, 26).
Laboratory Diagnosis
Identifying clinically relevant HHV-6 is hampered by the ubiquitous nature of infection and the spectrum of tissues and cell types that support persistent or latent infection in vivo. In addition, HHV-6 may integrate into human chromosomes (6, 52). Integration has been estimated to occur in less than 1% of individuals (27, 48) and has also been described in the transplant setting (5). The possibility of integrated HHV-6 must be considered when interpreting HHV-6 results in any population.
The diagnostic tests available for the detection of HHV-6 include serology, culture, antigenemia, immunohistochemistry, and nucleic acid amplification assays (Table 1). In general, serology has inadequate sensitivity and specificity in identifying acute infection in immunocompromised transplant patients, who have impaired ability to mount an effective immune response. The high HHV-6 seroprevalence rates in adults further limit the potential usefulness of serology after transplantation. Instead, methods utilizing direct viral detection, such as the detection of nucleic acids by polymerase chain reaction (PCR), are preferred for the detection of HHV-6 after solid organ transplantation. PCR of peripheral blood mononuclear cells (PBMC) is the most sensitive technique for detecting these viruses, but this type of assay may not be able to distinguish latent from active infection. In addition, many patients are leukopenic in the first few weeks after transplantation, especially after hematopoietic transplantation, when HHV-6 reactivation peaks, potentially limiting applicability of such assays in this population. The use of non-cellular samples, quantitative PCR, or methods to detect messenger RNA is recommended for the diagnosis of active HHV-6 infections. Either quantitative or qualitative methods may be used on non-cellular samples (serum or plasma) while quantitative methods (or methods aimed at detecting messenger RNA) are preferred when using cellular samples such as PBMC. It is important to also consider the potential detection of chromosomally-integrated HHV-6, a form of viral persistence characterized by very high levels of HHV-6 in blood samples (usually in millions of copies per ml whole blood), which may be misinterpreted as substantial active infection leading to unnecessary treatment (5). Detecting HHV-6 by PCR of hair follicles samples also indicates chromosomally-integrated HHV-6 (27, 48).
Because of the apparent low rate of clinical disease and the relatively high rate of subclinical viral reactivations, routine monitoring for HHV-6 after solid organ transplantation is not recommended. However there are certain clinical scenarios, such as encephalitis, which should prompt testing for HHV-6 (8). Wang et al.(51) demonstrated that HHV-6 was detected more frequently in the CSF of transplant recipients with encephalitis (5 of 22, or 23%) than in immunocompromised patients without encephalitis (1 of 107, or 0.9%). Although, there have been patients described with HHV-6 DNA detected in the CSF who are asymptomatic or relatively asymptomatic (56), the data from Wang et al suggest that detection of HHV-6 DNA in CSF of an HCT recipient if not all transplant recipients is potentially meaningful and that patients with CNS signs and symptoms should have their CSF investigated for HHV-6 as well as other pathogens.
ANTIVIRAL THERAPY
Currently, no antiviral compounds are approved for the treatment of HHV-6 infections. Foscarnet, ganciclovir and cidofovir are used clinically, based on in vitro data and anecdotal clinical reports. In vitro, HHV-6 is sensitive to achievable concentrations of ganciclovir, foscarnet, and cidofovir, although HHV-6A and HHV-6B variants demonstrate different susceptibilities (1, 53). Both HHV-6 variants are resistant to acyclovir and penciclovir.
The majority of HHV-6 infections are subclinical and transient, and therefore treatment of asymptomatic viral reactivation is not recommended. Treatment directed against HHV-6 should be initiated in the setting of HHV-6 encephalitis and should be considered for other clinical syndromes attributable to HHV-6. The International Herpes Management Forum recommends that HHV-6 be considered a cause of encephalitis, particularly in immunocompromised patients (8). The forum goes on to recommend ganciclovir and foscarnet either alone or in combination as first line therapy for treatment of HHV-6 related central nervous system illness. Cidofovir was not recommended as first line therapy in part because of potential toxicities.
Studies in order to define precise dosing and duration recommendations have not been performed. Dosing typical for CMV disease is often used ( Table 2 ). In the setting of HHV-6 encephalitis, some clinicians base duration of therapy on a minimum course of 3-4 weeks and factor in the patient’s clinical course and viral levels over time to define the ultimate course. It should be recognized however, that active viral replication in brain tissue may persist after levels in blood and cerebrospinal fluid have resolved (12). While chromosomally integrated HHV-6 is not treatable with antiviral agents (5, 19), a case of severe encephalomyelitis apparently successfully treated with foscarnet and ganciclovir in the setting of chromosomally integrated HHV-6 has been reported (50). Although the authors acknowledge the lack of certainty that HHV-6 caused the encephalitis in this case, it raises the possibility that HHV-6 may be able to cause disease and be treated in a patient with chromosomal integration. As in the treatment of most cases of opportunistic infections, strong consideration should be given to reducing the degree of pharmacologic immunosuppression when treating HHV-6 disease. This will allow the immune system to develop HHV-6 specific immunity that is needed for adequate control of infection. Although there is no direct evidence to support this strategy, it is assumed that the degree of immunosuppression is a risk factor that led to HHV-6 reactivation and clinical disease.
ENDPOINTS FOR MONITORING THERAPY
There have been no studies performed to define endpoints for monitoring therapy.
VACCINES
There are no vaccines currently available.
ANTIVIRAL PROPHYLAXIS
There is insufficient evidence to recommend the routine use of antiviral prophylaxis or preemptive therapy for HHV-6 infection. Since the majority of HHV-6 infections after transplantation are subclinical, antiviral prophylaxis or preemptive therapy are currently of questionable benefit. However, indirect evidence suggests that anti-CMV prophylaxis with ganciclovir-containing regimens has been associated with a lower rate and degree of HHV-6 detection (29, 37, 39, 49), although this finding has not been uniform (13). Hence, the true in vivo efficacy of current antiviral agents on HHV-6 infection and replication has not been conclusively or directly demonstrated, thereby raising further questions on the potential clinical benefit or utility of prophylaxis or preemptive therapy.
INFECTION CONTROL MEASURES
HHV-6 is ubiquitous and the vast majority of older children and adults are infected with latent virus. The virus is present in multiple cell and tissue types and it is shed in saliva. Special isolation precautions are not required for patients with HHV-6. The Centers for Disease Control and Prevention’s “Standard Precautions” are based on the principle that all blood, body fluids, secretions, excretions except sweat, non-intact skin, and mucous membranes may contain transmissible infectious agents (45). Standard Precautions include infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which healthcare is delivered. Standard precautions call for the use of personal protective equipment depending on the anticipated exposure and should be adequate for preventing transmission of HHV-6 in the healthcare setting.
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Table 1: Methods for diagnosis of HHV-6 and their advantages and disadvantages
| Assay | Advantages | Disadvantages/Limitations |
|---|---|---|
| Culture | Positive results represent active infection or replication
Allows to distinguish between subtypes A and B |
Technically difficult
Long turn-around time does not allow for real-time clinical management |
| PCR | Sensitive and specific for HHV-6
Rapid turn-around time to allow real-time clinical management
|
Risk of contamination (use of closed PCR system reduces this risk)
Lack of standardization among PCR assays |
| Plasma | Correlates well with diagnostic and clinical indicators of active viral infection and with virus isolation after transplantation
Technically easyAllows to distinguish between subtypes A and B |
|
| PBMC | Allows to distinguish between subtypes A and B | If not using RT-PCR, need to distinguish between latent and active infection by quantitative cut points or by setting sensitivity threshold
Negative results may be difficult to interpret in lymphopenic patients (HCT recipients early after transplant) |
| RT-PCR | Positive results represent active infection or replication |
|
| Serology | ||
| Standard |
|
Immunocompromised populations do not reliably mount antibody response
Interference of maternal antibody around time of primary infectionDoes not distinguish between types A and B |
| Avidity Assays | Avidity assays are able to distinguish between antibody associated with primary versus established infection. | Does not distinguish between types A and B |
Table 2: Antiviral agents with HHV-6 activity. Rigorous studies have not been performed to define optimal dosing and duration of therapy.
Dosing typical for CMV disease is often used and is represented in this table
| Agent | Indication | Dose | Duration |
|---|---|---|---|
| Ganciclovir* | 1st line therapy for HHV-6 associated disease | 5 mg/kg every 12 hours | Not defined, but should be guided by clinical and virologic assessments |
| Foscarnet | 1st line therapy for HHV-6 associated disease | 90 mg/kg every 12 hours (or 60 mg/kg every 8 hours) | Not defined, but should be guided by clinical and virologic assessments |
| Cidofovir | Consider if concern for resistance is present (rare) | 5 mg/kg every week | Not defined, but should be guided by clinical and virologic assessment |
Guided Medline Search for
Singh N, Carrigan DR. Human Herpesvirus-6
Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infectious Diseases 2007;7:460-472.
Sun HY, et al. Pharmacotherapy of post-transplant viral infections. Expert Opin Pharmacother 2008;9(14):2409-2421.
GUIDED MEDLINE SEARCH FOR RECENT REVIEWS
Berger S. Emergence of Infectious Diseases into the 21st Century, 2008.