Human Herpesviruses 6 and 7
Epidemiology and risk factors
Human herpesvirus 6 (HHV-6) and HHV-7 are lymphotropic β-herpesviruses that infect the majority of humans during the first few years of life. Primary HHV-6 and HHV-7 infections may be asymptomatic or manifest clinically as febrile illness associated with rash, diarrhea, respiratory symptoms, or seizures (1,2). HHV-6 exists as two variants; HHV-6A and HHV-6B. The latter variant is responsible for the majority of documented primary infections in children (1) and reactivation events after transplantation (3). HHV-6 and HHV-7 infections result in lifelong latency in mononuclear cells, which eventually serve as reservoirs for endogenous viral reactivation or as potential vectors of transmission to susceptible individuals (4). In less than 1% of infected individuals, HHV-6 persistence occurs as a result of the integration of the virus into the host chromosome (5).
Active HHV-6 and HHV-7 infections after solid organ transplantation occur either as primary infections (6) or secondary reactivation of latent virus (7). Primary HHV-6 and HHV-7 infections may be allograft-transmitted or occur as a result of natural transmission in the community (8). Since the seroprevalences of HHV-6 and HHV-7 are estimated to be over 90% in adults (2,4,9), most infections after transplantation are believed to result from the reactivation of endogenous latent virus. Pediatric transplant recipients, especially those younger than 2 years of age, however, may be HHV-6 and HHV-7 seronegative prior to transplantation and therefore are at risk of primary donor-allograft transmitted infection (8).
Precise estimation of the frequencies of active HHV-6 and HHV-7 infections after transplantation has been hampered by the use of a multitude of different diagnostic assays in clinical studies and the inability of some of these tests to distinguish active from latent infection. As a result, the estimated rates of HHV-6 infection after solid organ transplantation have varied widely between 20 and 55%. (3,10,11) There is less data on the rate of active HHV-7 infection after solid organ transplantation, although it has been estimated to occur in 0–46% of patients (3). Reactivation of both viruses occurs relatively early, generally within the first 2–4 weeks after solid organ transplantation (3,10,11).
The consequences of HHV-6 and HHV-7 infections after transplantation are classified into direct and indirect effects. Overt clinical disease directly due to HHV-6 has been estimated to occur in less than 1% of patients (12,13). Most of these have been due to HHV-6B, although a few cases of HHV-6A associated disease have been reported (14). In this setting, HHV-6 may be manifested as a febrile syndrome accompanied by some degree of bone marrow suppression, an illness similar to CMV syndrome (15,16). In some cases, HHV-6 and HHV-7 have been detected in the blood of patients with clinical syndromes attributable to CMV disease (16). To what extent HHV-6 and HHV-7 may be directly causing clinical symptoms in these patients is not clear. HHV6 has also been reported as a cause of febrile dermatosis (17), hepatitis (14), gastroduodenitis (18), colitis (19), pneumonitis (20) and encephalitis (20) after solid organ transplantation. In contrast, symptomatic disease due to HHV-7 is not well documented, although a few cases of febrile syndromes and acute myelitis have been described in transplant recipients (16,21,22).
In addition to direct effects, HHV-6 and HHV-7 may cause important indirect effects, possibly as a result of the immunomodulatory effects of active viral infection. Both HHV-6 and HHV-7 have been associated with CMV disease (23–25). HHV-6 has also been associated with fungal and other opportunistic infections (26), early fibrosis due to hepatitis C virus recurrence after liver transplantation (27), and a higher mortality rate after liver (28) and heart-lung transplantation (29). Both HHV-6 and HHV-7 have been associated with bronchiolitis obliterans syndrome after lung transplantation (30). There are conflicting data on the association between HHV-6 and HHV-7 infections with allograft rejection and dysfunction (31,32).
Risk factors for HHV-6 and HHV-7 infections are not completely defined. Given the high seroprevalence of both viruses, 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 (33), potentially through prolonged suppression of memory responses (34). Certain specific agents, including muromunab-CD3 (OKT3) and alemtuzumab have been associated with active HHV-6 infection after transplantation (35). Primary infections, presumably of donor origin, may occur in seronegative transplant recipients, and a few patients have developed fatal primary HHV-6 infections (30). Acute HHV-6 infection has also developed in patients who received liver transplantation for HHV-6 associated acute fulminant liver failure (36).
The diagnostic tests available for the detection of HHV-6 and HHV-7 include serology, culture, antigenemia, immunohistochemistry and nucleic acid amplification assays (Table 1). While serology may be used to identify nonimmune susceptible individuals, particularly young children, the test 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 and HHV-7 seroprevalence rates in adults further negates the potential usefulness of serology after transplantation. Therefore, serology has a very limited utility in the diagnosis of acute HHV-6 and HHV-7 infection after solid organ transplantation (III) (3). Instead, methods exploiting direct viral detection, such as the detection of nucleic acids by polymerase chain reaction (PCR), are preferred for the detection of HHV-6 and HHV-7 after solid organ transplantation (II-2) (16). 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. The use of noncellular samples, quantitative PCR, or methods to detect messenger RNA is recommended for the diagnosis of active HHV-6 and HHV-7 infections (III) (3). Either quantitative or qualitative methods may be used on noncellular samples (serum or plasma) while quantitative methods (or methods aimed at detecting messenger RNA) are preferred when using cellular samples (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, which may be misinterpreted as substantial active infection leading to unnecessary treatment (5). Because of the apparent low rate of clinical disease and the relatively high rate of subclinical viral reactivations, it is not recommended to perform routine monitoring for HHV-6 and -7 after solid organ transplantation (III).
|Recommendations||Level of evidence|
|HHV-6 and HHV-7|
|Diagnosis||Viral serologies are not helpful in the diagnosis of acute HHV-6 and HHV-7 infections after solid organ transplantation||III|
|Direct viral detection, such as the detection of nucleic acids by PCR, are preferred methods for diagnosis of HHV-6 and HHV-7||II-2|
|Quantitative or qualitative PCR methods may be used on non-cellular samples (serum or plasma) while quantitative methods or detection of messenger RNA are preferred when using cell-based clinical samples (e.g. PBMC)||III|
|Routine monitoring for HHV-6 and HHV-7 infections after solid organ transplantation is not recommended||III|
|Treatment||The majority of HHV-6 and HHV-7 infections are asymptomatic, transient, and do not require antiviral treatment||II-2|
|Treatment for HHV-6 should be initiated in the setting of HHV-6 encephalitis and should be considered for other syndromes attributable to HHV-6||III|
|Treatment of HHV-6 and HHV-7 should include reduction in the degree of immunosuppression||III|
|Prevention||Antiviral prophylaxis or preemptive antiviral therapy for HHV-6 or HHV-7 infections are not recommended after transplantation||III|
|Diagnosis||Serology is of limited utility in the diagnosis of HHV-8 after solid organ transplantation||III|
|Pre transplant donor and recipient HHV-8 serology may stratify the risk of disease after transplantation in endemic areas||II-2|
|Immunohistochemistry using monoclonal antibodies against HHV-8 antigens is useful for the pathological diagnosis of KS and other angiogenic proliferative diseases||II-2|
|Nucleic acid amplification assays to quantitate HHV-8 load in clinical samples is preferred for the diagnosis of active HHV-8 replication||II-2|
|Quantification of HHV-8 load could be used for monitoring transplant patients with KS||III|
|Treatment||Reduction or cessation of immunosuppression should be a first-line therapy||II-3|
|Conversion of immunosuppressive regimen from calcineurin inhibitors to sirolimus (rapamycin) should be considered||II-3|
|Patients whose lesions do no not regress despite reduction in immunosuppression may require surgical excision, radiation therapy or cytotoxic chemotherapy||II-2|
|Prevention||HHV-8 serologic screening of donors and recipients may be considered to assess risk, especially in geographic regions with high rates of infection||II-2|
|In HHV-8 seropositive recipients or those who receive an organ from HHV-8 seropositive donor, monitoring of HHV-8 load after transplantation may be useful to determine the risk of disease||III|
|Avoidance of over-immunosuppression in high-risk individuals and in those with detectable HHV-8 viremia may be beneficial||III|
The majority of HHV-6 and HHV-7 infections are subclinical and transient, and therefore treatment of asymptomatic viral reactivation is not recommended (II-2) (Table 1). Likewise, HHV-6 and HHV-7 co-infections with CMV do not require therapy in addition to the treatment given for CMV infection and disease (37). However, 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 (III). Currently, however, no antiviral compounds have been approved for the treatment of HHV-6 and HHV-7 infections, although foscarnet, ganciclovir and cidofovir have been 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 (38). HHV6-B is usually susceptible to both ganciclovir and foscarnet. However, proportionately more isolates of HHV6-A are likely to be resistant to ganciclovir than to foscarnet. HHV-7 appears resistant to ganciclovir in vitro, and may not be inhibited with achievable concentrations of ganciclovir (38). Both HHV-6 and HHV-7 are resistant to acyclovir and penciclovir (38). Antiviral treatment should be complemented by a reduction in the degree of pharmacologic immunosuppression (III).
There is insufficient evidence to recommend the routine use of antiviral prophylaxis or preemptive therapy for HHV-6 or HHV-7 infections (III) (Table 1). Since the vast majority of HHV-6 and HHV-7 infections after solid organ transplantation are subclinical, antiviral prophylaxis or preemptive therapy are currently of questionable benefit (III). Indirect evidence suggests that the prevalence of HHV-7 infection was not affected by the administration of oral or intravenous ganciclovir or valganciclovir prophylaxis, which was used for the prevention of CMV disease in cohorts of solid organ transplant recipients (39). In contrast, anti-CMV prophylaxis with ganciclovir-containing regimens has been associated with a lower rate and degree of HHV-6 reactivation (39), although others have disputed these findings (40). Hence, the true in vivo efficacy of current antiviral agents on HHV-6 and HHV-7 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.
A full understanding of the clinical impact of HHV-6 and HHV-7, including the direct effects as well as interactions with CMV, and other immunomodulatory effects, requires large prospective clinical studies. By assessing the magnitude of their clinical impact, one gains insight into the potential need for routine monitoring for these viruses after transplantation, and the potential need to treat even asymptomatic infections. The in vivo efficacy of currently available antiviral compounds against HHV-6 and HHV-7 also requires further study.