Etiology

HHV-6 and HHV-7 are the sole members of the Roseolovirus genus in the Betaherpesvirinae subfamily of human herpesviruses. Human cytomegalovirus (CMV), the only other β-herpesvirus, shares limited sequence homology with HHV-6 and HHV-7. Morphologically all human herpesviruses are composed of an icosahedral nucleocapsid, protein-dense tegument, and lipid envelope. Within the nucleocapsid, HHV-6 and HHV-7 each contain large, linear, double-stranded DNA genomes that encode >80 unique proteins.

Two strain groups of HHV-6 have been recognized, HHV-6 variant A and variant B. The genomes of HHV-6 A and B are highly conserved, with approximately 90% sequence identity. However, they can be distinguished by restriction fragment length polymorphisms, reactivity with monoclonal antibodies, differential growth in tissue culture cell lines, and epidemiology. Accordingly, some researchers propose that they should be separate viruses. Although the frequency of detection of HHV-6 variant A DNA differs among studies, variant B is the overwhelmingly predominant strain found in both normal and immunocompromised hosts by both culture and polymerase chain reaction (PCR). Primary infection with HHV-6 variant A has been detected in children in Africa. It is not clear whether the differences in the detection of HHV-6 variant A DNA and variant B DNA relate to different tissue tropism, differences in mode or age of acquisition, differences in the ability to cause human disease, or the geographical location of the population studied.

Epidemiology

Primary infection with HHV-6 is acquired rapidly by essentially all children following the loss of maternal antibodies in the first few months of infancy, 95% of children being infected with HHV-6 by 2 yr of age. The peak age of primary HHV-6 infection is 6-9 mo of life, with infections occurring sporadically and without seasonal predilection. Infection with HHV-7 is also widespread but occurs later in childhood and at a slower rate; only 50% of children have evidence of prior infection with HHV-7 by 3 yr of age. Seroprevalence reaches 75% at 3-6 yr of age. In a small study of children with primary HHV-7 infection, the mean age of the patients was 26 mo, significantly older than that of children with acute HHV-6 infection.

Although it is presumed that children acquire primary infection with HHV-6 and HHV-7 from the saliva of asymptomatic adults, congenital infection with HHV-6 occurs in 1% of newborns. Two mechanisms of vertical transmission of HHV-6 have been identified, transplacental infection and chromosomal integration (CI-HHV6). HHV-6 is unique among the human herpesviruses in that it is integrated at the telomere end of human chromosomes at a frequency of 0.2-2.2% of the population and is passed from parent to child via the germline. Chromosomal integration has been identified as the major mechanism by which HHV-6 is vertically transmitted, accounting for 86% of congenital infections, with one third due to HHV-6 variant A. The clinical consequences of chromosomal integration or transplacental infection with HHV-6 have yet to be determined. In one series of infants identified with HHV-6 congenital infection, no evidence of disease was present in the early neonatal period. Congenital infection with HHV-7 has not been demonstrated. DNA of both HHV-6 and HHV-7 has been identified in the cervical secretions of pregnant women, suggesting an additional role for sexual or perinatal transmission of these viruses. Breast milk does not appear to play a role in transmission of either HHV-6 or HHV-7.

Pathology/Pathogenesis

Primary HHV-6 infection causes a viremia that can be demonstrated by co-culture of the patient’s peripheral blood mononuclear cells (PBMCs) with mitogen-stimulated cord blood mononuclear cells. HHV-6 has a recognizable cytopathic effect, consisting of the appearance of large refractile mononucleated or multinucleated cells with intracytoplasmic and/or intranuclear inclusions. Infected cells exhibit a slightly prolonged life span in cultures; however, lytic infection predominates. HHV-6 infection also induces apoptosis of T cells and may lead to cell expiration via loss of mitochondrial membrane potential as well as alteration of interferon and retinoic acid-induced cell death signals. In vitro, HHV-6 can infect a broad range of cell types, including primary T cells, monocytes, natural killer (NK) cells, dendritic cells, and astrocytes. HHV-6 has also been documented to infect B-cell, megakaryocytic, endothelial, and epithelial cell lines. Human astrocytes, oligodendrocytes, and microglia have been infected with HHV-6 ex-vivo. The broad tropism of HHV-6 is consistent with the recognition that CD46, a complement regulatory protein present on the surface of all nucleated cells, is a cellular receptor for HHV-6. The CD4 molecule has been identified as a receptor for HHV-7. HHV-7 has been demonstrated to reactivate HHV-6 from latency in vitro. Whether this phenomenon occurs in vivo remains unknown.

Primary infection with HHV-6 and HHV-7 is followed by lifelong latency or persistence of virus at multiple sites. HHV-6 exists in a true state of viral latency in monocytes and macrophages. The detection of replicating HHV-6 in cultures of primary CD34+ hematopoietic stem cells has also been described, suggesting that cellular differentiation is a trigger of viral reactivation. This observation may be clinically significant because of the possibility that HHV-6 may cause either primary or reactivated infection during hematopoietic stem cell transplantation. Additionally, HHV-6 and HHV-7 infection may be persistent in salivary glands, and DNA for both HHV-6 and HHV-7 can be routinely detected in the saliva of both adults and children. HHV-7 can also be isolated in tissue culture from saliva, but HHV-6 cannot. HHV-6 DNA has been identified in the cerebrospinal fluid (CSF) of children both during and subsequent to primary infection as well as in brain tissue from immunocompetent adults at autopsy, implicating the central nervous system (CNS) as an additional important site of either viral latency or persistence. HHV-7 DNA has also been found in adult brain tissue but at a significantly lower frequency.

Clinical Manifestations

Roseola infantum (exanthem subitum, or sixth disease) is an acute, self-limited disease of infancy and early childhood. It is characterized by the abrupt onset of high fever, which may be accompanied by fussiness. The fever usually resolves acutely after 72 hr (“crisis”) but may gradually fade over a day (“lysis”) coincident with the appearance of a faint pink or rose-colored, nonpruritic, 2- to 3-mm morbilliform rash on the trunk (Fig. 248-1). The rash usually lasts 1-3 days but is often described as evanescent and may be visible only for hours, spreading from the trunk to the face and extremities. Because the rash is variable in appearance, location, and duration, it is not distinctive. Associated signs are sparse but can include mild injection of the pharynx, palpebral conjunctivae, or tympanic membranes and enlarged suboccipital nodes. In Asian countries, ulcers at the uvulopalatoglassal junction (Nagayama spots) are commonly reported in infants with roseola.