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K.N. Ward et al.
Human herpesvirus 6A and human herpesvirus 6B
The two species of HHV-6, HHV-6A and HHV-6B infect and establish latency in different cell types including CD4 positive T lymphocytes, monocytes, and other epithelial, fibroblastic and neuronal cells.2 No disease has been causally linked to HHV-6A, and its natural history is unknown. In contrast, HHV-6B primary infection is ubiq- uitous in the first two years of life sometimes causing exanthema subitum; subsequent viral latency gives the potential for reactivation and disease.
Chromosomally integrated human herpesvirus 6
As well as the almost universal postnatal acquisition of HHV-6B, in approximately 1% of humans the complete genome of HHV-6A or HHV-6B is integrated into a chro- mosomal telomere in every nucleated cell in the body and is transmitted through Mendelian inheritance.3,4 Although HHV-6A is rare in the general population, HHV-6A and HHV-6B are encountered in approximately one-third and two-thirds of individuals with CIHHV-6, respectively.5 Telomeric integration sites have been identified on differ- ent chromosomes using fluorescence in situ hybridization (FISH).6 Integration is normally restricted to a particular chromosome per individual but very rarely two sites, if inherited from both parents.3
Human herpesvirus 6 DNA detected in blood usually indicates virus replication. However, in individuals with CIHHV-6, viral DNA in latent form originating from human chromosomal DNA is persistently detected at high levels in whole blood as well as in “cell free” samples such as serum and cerebrospinal fluid (CSF), since the latter contain cellular DNA released from damaged cells during sample preparation.7,8 Although HHV-6B encephalitis is an accepted, albeit rare, complication of primary HHV-6B infection in young children, HHV-6 DNA in the CSF of older immunocompetent children and adults is most likely due to latent virus originating from CIHHV-6 rather than central nervous system (CNS) infection.8,9
Chromosomally integrated human herpesvirus 6 and potential for disease post-hematopoietic stem cell transplantation
There is limited evidence of symptomatic reactivation of CIHHV-6. One report demonstrated CIHHV-6A reacti-
vation in a child with severe combined immunodeficiency and hemophagocytic syndrome pre-HSCT and thrombot- ic microangiopathy post-HSCT.10 Two other reports from settings other than HSCT give evidence for symptomatic reactivation in a patient treated with a histone deacetylase inhibitor11 and a patient who received a liver transplant from a donor with CIHHV-6A.12
Despite the above case of reactivation with accompany- ing morbidity post-HSCT,10 this has not been reported in the few other cases where CIHHV-6 was identified in the donor or recipient,13-16 and the frequency and type of dis- eases caused by CIHHV-6 in HSCT recipients remain unknown. A recent study of 87 patients with CIHHV-6 in HSCT donors and/or recipients demonstrated an associa- tion with acute graft-versus-host disease (GvHD) and cytomegalovirus (CMV) reactivation, but there was no effect on overall or non-relapse mortality.17 Neither has an increased frequency of CIHHV-6 been identified in a range of hematologic malignancies.17-21 None of these studies was designed to address the likelihood that integration into different chromosomal sites might have different pathological consequences and vary according to HHV-6 species.
Human herpesvirus 6 and disease in patients with hematologic malignancies or post-hematopoietic stem cell transplantation
In patients with hematologic malignancies without HSCT, there is little evidence that HHV-6 causes disease. Post-HSCT the high frequency of HHV-6B reactivation, plus the difficulty of identifying CIHHV-6, causes substan- tial challenges in determining the pathogenic role of HHV- 6 in disease. For autologous transplants, there are insuffi- cient data for a causal association with end-organ disease. However, after allogeneic HSCT, HHV-6B is associated with several syndromes and is a well recognized cause of encephalitis with high morbidity and mortality.
Definitions
Primary human herpesvirus 6 infection
This is defined as the first detection of HHV-6 replica- tion in an individual with no evidence of previous infec-
Table 1. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) grading system. Strength of a recommendation
Grade A
Grade B Grade C Grade D
Quality of evidence
Level I
Level II *
Level III
ESCMID strongly supports a recommendation for use
ESCMID moderately supports a recommendation for use ESCMID marginally supports a recommendation for use ESCMID supports a recommendation against use
Evidence from at least one properly designed randomized, controlled trial
Evidence from at least one well-designed clinical trial, without randomization; from cohort or case-controlled analytical studies
(preferably from more than one center); from multiple time series; or from dramatic results of uncontrolled experiments
Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports
of expert committees
*Added index for level II quality of evidence. • r: meta-analysis or systematic review of randomized controlled trials. • t: transferred evidence, i.e. results from different patient cohorts, or similar immune-status situation. • h: comparator group is a historical control. • u: uncontrolled trial. • a: published abstract (presented at an international symposium or meeting).
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