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Sixth Disease and the Ubiquity of Human Herpesviruses


Sixth Disease and the Ubiquity of Human Herpesviruses Charles Prober, M.D. Related article, page 768

Human herpesvirus 6 (HHV-6) is the cause of the sixth clinically distinct exanthematous disease of childhood. Measles virus, erythrogenic group A streptococci, and rubella virus are the causes of the first three diseases, and parvovirus B19 is the cause of the fifth disease. The origin of the fourth classic childhood illness, formerly referred to as Dukes’ disease, is controversial. Some medical historians believe that it probably represented misdiagnosed cases of rubella or scarlet fever, rather than a distinct illness. HHV-6 is so named because it was the sixth human herpesvirus to be identified. This family of large DNA viruses includes eight known human pathogens. In addition to HHV-6, these include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella–zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8) (see table). Herpesviruses have several common features. Each roughly spherical virion is 150 nm to 200 nm in diameter and consists of a 100-nm icosahedral nucleocapsid containing a core of linear, double-stranded DNA viral genome, spooled around a nucleoprotein central mass. The nucleocapsid is surrounded by a layer of amorphous, asymmetrically distributed material (tegument), which, in turn, is encased by a lipidcontaining envelope with multiple glycoprotein protrusions. The most important biologic property shared by all herpesviruses is their ability to establish a persistent state following primary infection. This capacity means that once a person has become infected with a herpesvirus, he or she is forever susceptible to periodic viral reactivation. Reactivation results in the emergence of transmissible virus. The site of viral latency varies. Even in the absence of signs or symptoms of infection, common sites of periodic

appearance of herpesviruses include oral secretions (for HSV-1, EBV, CMV, HHV-6, and HHV-7), genital secretions (HSV-2, CMV, and HHV-6), urine (CMV), mononuclear cells (CMV, HHV-6, and HHV-7), and breast milk (CMV and HHV-7). Host immunity influences both the likelihood of reactivation and the severity of clinical illness. In general, the greater the degree of immune impairment, the more substantial the consequences of herpesvirus reactivation. Given the high incidence of all herpesvirus infections (except HHV-8 infection) and the biologic phenomenon of latency, the ubiquity of these viruses is readily apparent. In the United States, infections caused by HSV-1 begin in infancy, and at least 50 percent of young adults have been infected. Infections caused by HSV-2 begin with the onset of sexual activity, and an estimated 25 percent of U.S. adults have contracted infection. EBV infections increase in frequency during adolescence, and most of the population is infected by middle age. CMV is the most common cause of congenital infection, with 1 percent of all newborns infected; postnatal infections begin to occur within the first few weeks of life, and by early adulthood approximately 50 percent of the population is seropositive. Before the development of a vaccine for VZV, chickenpox (VZV infection) occurred in virtually all people by late childhood; the epidemiology of infection has been changing since the introduction of universal vaccination. In this issue of the Journal, Zerr et al. (pages 768–776) note that approximately three quarters of children have been infected with HHV-6 by two years of age. Data from other studies suggest that infection with HHV-7 has a similar epidemiologic pattern. Clearly, herpesvirus infections are omnipresent, and at any given time, a substantial proportion of the population is shedding one or more of these infectious agents, maintaining the chain of transmission and the high prevalence of infection. Even though the majority of infections caused by Dr. Prober is a professor of pediatrics and of microbioloherpesviruses are asymptomatic or mild (see figure), gy and immunology at Stanford University School of the morbidity attributable to these agents remains Medicine and scientific director of the Glaser Pediatric substantial. Furthermore, death due to herpesvirusResearch Network — both in Stanford, Calif.

n engl j med 352;8

february 24, 2005

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Sixth Disease and the Ubiquity of Human Herpesviruses

PERSPECTIVE Human Herpesviruses.


Approximate Seroprevalence among Young U.S. Adults (%)

Common Infections

Mode of Transmission

Herpes simplex virus type 1


Herpes labialis, herpes Neuronal cells, espe- Contact with secretions, whitlow, herpetic kercially trigeminal especially oral atitis, herpes simplex ganglia encephalitis

Herpes simplex virus type 2


Herpes genitalis, herpes Neuronal cells, espe- Contact with secretions, proctitis, neonatal cially sacral ganespecially genital herpes glia

Varicella–zoster virus


Chickenpox, herpes zoster (shingles)

Neuronal cells, espe- Contact with infected skin cially posterior lesions; respiratory root ganglia route for chickenpox

Epstein–Barr virus


Infectious mononucleosis, prolonged fever, multiorgan manifestations

B lymphocytes

Contact with oral secretions, blood, or transplanted organs



Infectious mononucleosis, prolonged fever

Monocytes, macrophages

Contact with oral or genital secretions, urine, breast milk, blood, or transplanted organs

Human herpesvirus 6


Febrile illness, roseola

T lymphocytes

Contact with oral secretions

Human herpesvirus 7


Febrile illness, roseola

T lymphocytes

Contact with oral secretions or breast milk

Human herpesvirus 8


Kaposi’s sarcoma

Not established

Contact with bodily secretions

es is a major issue for the ever-increasing population of immunocompromised persons. HSV-1 infections cause herpes labialis, whose manifestations range from periodic mild discomfort accompanied by a few perioral vesicles to a severe infection necessitating hospitalization. HSV-1 is also responsible for most cases of herpetic whitlow and other cutaneous eruptions (e.g., herpes gladiatorum and eczema herpeticum), herpetic keratitis, and a severe form of nonseasonal, focal encephalitis. HSV-2 is the predominant cause of genital herpes, herpes proctitis, and neonatal herpes infections. The most common manifestation of EBV infection is infectious mononucleosis, although EBV has also been proposed as a cause of myriad diseases involving virtually every organ in the body. The manifestations of CMV infection overlap substantially with those of EBV infection, and both viruses are important causes of prolonged febrile illnesses in normal hosts. VZV causes chickenpox and, with reactivation, herpes zoster. The pathogenic role of herpesviruses in some


Site of Persistence

types of cancer is well established (e.g., EBV has a role in Burkitt’s lymphoma in Africa, nasal pharyngeal carcinoma, and post-transplantation lymphoproliferative disorder, and HHV-8 has a role in Kaposi’s sarcoma). In contrast, the role of these viruses in several chronic diseases, such as multiple sclerosis and the chronic fatigue syndrome, continues to be debated. Although HHV-6 was initially isolated in 1986 from the B lymphocytes of immunocompromised adults, within two years it was described as the cause of most cases of roseola (sixth disease). The classic clinical picture of roseola, dating back to 1910, is three to five days of high fever in an infant, followed by the acute onset of a rose-pink, nonpruritic, macular rash, predominantly on the neck and trunk. Because of the abrupt onset of the rash, the disease was called exanthema subitum (“subitum” meaning “sudden” in Latin). Subsequent reports identified HHV-6 as a major cause of illness in young children who were brought to emergency departments for the evaluation of fe-

n engl j med 352;8

february 24, 2005

Downloaded from on September 29, 2009 . Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Sixth Disease and the Ubiquity of Human Herpesviruses


HSV- 1

HSV- 2


HHV- 6


Clinical Characteristics of Herpesviruses. The image of Epstein–Barr virus (EBV) infection shows a child with exudative pharyngitis associated with infectious mononucleosis, the image of herpes simplex virus type 1 (HSV-1) infection shows a paronychial infection (herpetic whitlow), the image of herpes simplex virus type 2 (HSV-2) infection shows ulcerative lesions on the vulva (genital herpes), the image of varicella–zoster virus (VZV) infection shows vesicular lesions in a dermatomal distribution (herpes zoster), the image of human herpesvirus 6 (HHV-6) infection shows a child with the rash of roseola, and the image of cytomegalovirus (CMV) infection shows chorioretinitis consistent with infection in an immunocompromised host. EBV courtesy of Stanley Martin, M.D.

ver. Depending on the specific age range of the population studied, 10 to 50 percent of febrile illnesses leading to an emergency room visit have been attributed to HHV-6 infection, the peak age of infection being six to nine months. The consequences of HHV-6 infection diagnosed in children in emergency departments may be substantial; among those younger than two years of age who

n engl j med 352;8

have HHV-6 infection, more than 10 percent have febrile seizures, and more than 10 percent are hospitalized. HHV-6 appears to account for approximately one third of febrile seizures in children in this age group. The lack of a prospective, population-based study of HHV-6 beyond the acute care setting had limited our understanding of the full spectrum of illness that is attributable to this virus. Zerr et al. have addressed this shortcoming. Using an intensive study design that included the collection of weekly samples of saliva for the diagnosis of HHV-6 infection on the basis of quantitative DNA testing, the Seattle investigators prospectively followed a cohort of 277 infants from birth through two years of age. The frequency and types of clinical illness associated with HHV-6 infection were determined on the basis of daily illness logs, and symptoms were compared with those in age-matched controls who were not acutely infected with HHV-6. More than three quarters of the infants were infected with HHV-6 by the second year of life, and more than 90 percent of the infections were associated with symptoms. Fever and fussiness were the most common manifestations of infection; roseola was diagnosed in about one quarter of the study population. Almost 40 percent of the children were evaluated by a physician for symptoms coincident with their HHV-6 infection. In contrast to studies involving febrile young children recruited from emergency departments, this study showed that seizures were not a feature of HHV-6 infection. Remarkably, HHV-6 DNA remained detectable at moderately high levels in saliva for at least 12 months after the initial infection. Although the precise relationship between the quantity of viral DNA and transmissible virus has not been established, previous studies have indicated that saliva is the principal source of infectious virus. Previous studies also have demonstrated that persons who are seropositive for EBV, CMV, HSV-1, and HSV-2 shed reactivated virus frequently throughout their lives. Taken together, these studies underscore an inescapable epidemiologic fact: herpesviruses are ubiquitous.

february 24, 2005

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HHV-6 causa de roseola