Roseola (Human Herpesviruses 6 and 7)
Human herpesvirus 6 (HHV-6) was discovered in 1986, 22 yr after the discovery of the 5th human herpesvirus (Epstein-Barr virus). Six isolates of a new virus were identified in the peripheral blood mononuclear cells (PBMCs) of adult patients with AIDS or lymphoproliferative diseases. In 1990, human herpesvirus 7 (HHV-7) was identified in the peripheral blood mononuclear cells of an HIV-uninfected adult. HHV-6 is the etiologic agent for most cases of roseola infantum (exanthem subitum, or sixth disease), and also is associated with other diseases in normal and immunocompromised patients. Disease associations for HHV-7 are fewer; only its role in some cases of roseola is well established.
Roseola was first established as a distinct illness at the turn of the 20th century. Until recently, no pathogen could be consistently identified as the agent responsible for roseola. However, it is now clear that primary infection with HHV-6, and less frequently HHV-7, causes the majority of cases of roseola. In studies of children with roseola from Europe and Asia, HHV-6 was responsible for approximately two thirds of cases and HHV-7 caused one fourth of cases. Other viruses (e.g., echovirus 16) probably account for the remainder.
HHV-6 and HHV-7 belong to the ß-herpesvirus subfamily of herpesviruses, which includes human cytomegalovirus (CMV). HHV-6 and HHV-7 share physical and biologic characteristics with other herpesviruses, including a large double-stranded DNA genome, the presence of a nucleocapsid, and the establishment of latency after primary infection. HHV-6 is essentially colinear with HHV-7, and both viruses share much homology with CMV. The principal target cells for HHV-6 and HHV-7 infection in vivo are CD4 T cells; HHV-6 can also infect other cells, including CD8 (suppressor) T cells, natural killer T cells, d? T cells, glial cells, epithelial cells, monocytes, megakaryocytes, and endothelial cells. HHV-6 and HHV-7 are typically cultivated in vitro in mitogen-stimulated human mononuclear cells (isolated from cord blood or peripheral blood) and can be identified by the development of large balloon-like cells accompanied by cell lysis. Two distinct types of HHV-6 (types A and B) exist. Type B causes more than 99% of HHV-6–associated roseola cases. Latent type A virus can be found in immunodeficient as well as healthy patients and may reactivate in severely ill adult patients. However, it has not been consistently linked with any disease.
Primary HHV-6 infection occurs early in life. More than 90% of newborn infants are HHV-6 seropositive, reflecting transplacental transfer of maternal antibodies. By 4–6 mo of age, the prevalence drops significantly (0–60%). By 12 mo of age, 60–90% of children possess antibodies to HHV-6, and by 3–5 yr, 80–100% of children are seropositive. Peak acquisition of primary HHV-6 infection, from 6–15 mo of age, corresponds with peak acquisition of roseola. Less than half of HHV-6 infections in U.S. infants are clinically recognizable as roseola, whereas 80% of Japanese infants with primary HHV-6 infection develop roseola. Primary infection with HHV-7 occurs slightly later than HHV-6 infection, with 45–75% of children infected by 2 yr of age and 90% by 7–10 yr of age.
Roseola can develop in children year-round; some series indicate a higher incidence during spring and fall months. Unlike some of the other childhood exanthems, children with roseola rarely report contact with other affected children, and outbreaks are uncommon. Sex, race, and geography do not play an important role in acquisition of roseola. The incubation period averages 10 days (range of 5–15 days).
Most adults excrete HHV-6 and HHV-7 in saliva and may serve as primary sources for virus transmission to children. Women excrete HHV-6 and HHV-7 in the genital tract at low rates, but sexual transmissibility has not been demonstrated. There is evidence that HHV-6 can be transmitted in utero, although this is a rare occurrence and no malformations have been noted. No congenital HHV-7 infections have been described. HHV-6 has been transmitted to susceptible infant transplant recipients via infected donor bone marrow or solid organ. There is no evidence that infection is spread by breast milk or blood transfusion.
Little is known regarding the pathogenesis of infections associated with HHV-6 and HHV-7, including roseola. Virus is probably acquired from the saliva of healthy persons and enters the host through the oral, nasal, or conjunctival mucosa. Cellular receptors for both viruses have been identified: HHV-6 uses the CD46 receptor (also used by measles virus), and HHV-7 uses the CD4 receptor (also used by HIV-1). Following viral replication at an unknown site, a high level of viremia develops in PBMCs. After acute infection, HHV-6 and HHV-7 establish latency in blood mononuclear cells and possibly in the salivary glands, kidneys, lungs, and central nervous system. Both viruses may evade the immune system through downregulation of the major histocompatibility complex (MHC) type I response. The basis for the unique pattern of rash after resolution of fever in children with roseola has not been established.
HHV-6 can suppress all cellular lineages within the bone marrow, and active HHV-6 infection is associated with bone marrow suppression in bone marrow transplant patients. HHV-6 infection also has significant effects on the immune system, including enhancement of natural killer (NK) T-cell activity, suppression of PBMC proliferation, and induction of a proinflammatory cytokine response.
Roseola is the prototypical HHV-6 and HHV-7 infection, although nonspecific infections are common.
ROSEOLA INFANTUM (EXANTHEM SUBITUM).
Roseola is a mild febrile, exanthematous illness occurring almost exclusively during infancy. More than 95% of roseola cases occur in children younger than 3 yr, with a peak at 6–15 mo of age. Transplacental antibodies likely protect most infants until 6 mo of age.
Infants with classic roseola exhibit a unique constellation of findings displayed over a short period of time. Consequently, classic roseola is infrequently confused with other childhood exanthems.
The prodromal period of roseola is usually asymptomatic but may include mild upper respiratory tract signs, among them minimal rhinorrhea, slight pharyngeal inflammation, and mild conjunctival redness. Mild cervical or, less frequently, occipital lymphadenopathy may be noted. Some children may have mild palpebral edema. Physical findings during the prodromal stage have no clear relationship to roseola, and may simply reflect an accompanying respiratory viral infection.
Clinical illness is generally heralded by high temperature, usually ranging from 37.9 to 40°C (101–106°F), with an average of 39°C (103°F). Some children may become irritable and anorexic during the febrile stage, but most behave normally despite high temperatures. Seizures may occur in 5–10% of children with roseola during this febrile period. Infrequent complaints include rhinorrhea, sore throat, abdominal pain, vomiting, and diarrhea. In Asian countries, ulcers at the uvulopalatoglossal junction (Nagayama spots) are common in infants with roseola.
Fever persists for 3–5 days, and then typically resolves rather abruptly (“crisis”). Occasionally, the fever may gradually diminish over 24–36 hours (“lysis”). A rash appears within 12–24?hr of fever resolution. In many cases, the rash develops during defervescence or within a few hours of fever resolution. The rash of roseola is rose colored, as the name implies, and is fairly distinctive. However, it may be confused with exanthems resulting from rubella, measles, or erythema infectiosum. The roseola rash begins as discrete, small (2–5?mm), slightly raised pink lesions on the trunk and usually spreads to the neck, face, and proximal extremities. The rash is not usually pruritic, and no vesicles or pustules develop. Lesions typically remain discrete but occasionally may become almost confluent. After 1–3 days, the rash fades. Some children experience evanescent rashes that resolve within a few hours.
Subtle differences in clinical presentation have been noted between roseola associated with HHV-7 compared with HHV-6. These include a slightly older age, lower mean temperature, and shorter duration of fever in HHV-7-associated cases. However, these differences are insufficient to clinically distinguish HHV-6– from HHV-7–associated roseola. There are reports of children experiencing HHV-6–associated roseola followed later by HHV-7–associated roseola.
FEVER IN INFANTS WITHOUT CLASSIC ROSEOLA.
HHV-6 and HHV-7 account for a significant proportion of nonspecific febrile illnesses in infants. Studies among infants presenting to a hospital emergency room indicate that approximately 15% had primary HHV-6 or HHV-7 infection.
CENTRAL NERVOUS SYSTEM INFECTIONS.
Both HHV-6 and HHV-7 are neurotropic and can invade the CNS. Primary HHV-6 infection is responsible for one third of febrile seizures in infants. Most of these children (70–80%) do not subsequently experience a rash. Smaller studies suggest that HHV-7 also is associated with some febrile seizures. HHV-6 and HHV-7 are also associated with rare cases of encephalitis and meningoencephalitis. One large study noted HHV-6 DNA in cerebrospinal fluid from 6% of children and adults with focal encephalitis of unknown cause.
MONONUCLEOSIS-LIKE ILLNESS AND HEPATITIS.
Several heterophile-negative mononucleosis-like infections associated with HHV-6 have been reported in adults. HHV-6 and HHV-7 may rarely cause clinical symptoms of hepatitis. Some infants have developed HHV-6-associated liver failure, and one fatal case of hepatitis was reported in a neonate after maternal transmission of HHV-6.
INFECTIONS IN IMMUNOCOMPROMISED PATIENTS.
Numerous severe and occasionally fatal HHV-6–associated infections (encephalitis and pneumonitis) have occurred in immunocompromised patients, including patients with AIDS or organ transplants. These have occurred predominantly in stem cell transplant recipients and usually reflect reactivated HHV-6 infection. Recent studies suggest that concomitant HHV-6 and HHV-7 infections may augment CMV-associated disease following organ transplantation.
Because HHV-6 shares CD4 cell tropism with HIV, upregulates HIV, and stimulates in vitro replication of HIV, there has been considerable interest in the role of HHV-6 as a cofactor for clinical progression of AIDS. Epidemiologic studies in adults do not support a significant role for HHV-6 as a cofactor, but one small pediatric study does suggest more rapid progression of immune deficiency in HIV/HHV-6 coinfected patients. Further prospective studies are necessary to assess the impact of HHV-6 on HIV-infected children.
OTHER DISEASES POSSIBLY ASSOCIATED WITH HHV-6 OR HHV-7.
Rash illness without fever has been described in a small number of infants with primary HHV-6 infection. Other small studies or case reports have suggested that HHV-6 may be associated with some cases of hemophagocytic syndrome, intussusception, idiopathic thrombocytopenic purpura, recurrent aphthous stomatitis, myocarditis, and disseminated disease. There are conflicting data linking HHV-7 and pityriasis rosea, a benign exanthematous illness. HHV-6, like several other infectious agents, has been linked to multiple sclerosis by some, but not all, investigators.
HHV-6 DNA has been detected in various malignancies, including non-Hodgkin lymphoma, Hodgkin disease, cervical and oral carcinoma, and leukemia. However, no consistent etiologic relationship has been established with any of these cancers.
The most important reason for establishing the diagnosis of roseola is to differentiate this generally mild illness from other potentially more serious childhood rash illnesses such as measles. It is also important to identify other, more serious illnesses caused by HHV-6, such as encephalitis and pneumonitis, especially in immunocompromised patients, for timely consideration of antiviral therapy.
The diagnosis of roseola can be established primarily on the basis of age, history, and clinical findings. HHV-6- and HHV-7-associated roseola cases cannot be distinguished solely on clinical grounds. Specific testing for HHV-6 or HHV-7 infection may be performed using laboratory methods, including serology, virus culture, antigen detection, and polymerase chain reaction (PCR).
HHV-6 serologic testing is available from many commercial laboratories; few offer HHV-7 serology. An HHV-6 immunoglobulin (Ig) M response typically develops by the 5th–7th day of illness, peaks at 2–3 wk, and resolves within 2 mo. Unfortunately, the accuracy of currently available IgM tests varies widely, and none have been sufficiently evaluated to provide unequivocal evidence of acute HHV-6 infection. Seroconversion of HHV-6 or -7 IgG antibodies in serum samples collected 2–3 wk apart is a more reliable means of establishing primary infection, but is not timely. Fourfold increases or decreases in HHV-6 or -7 IgG antibodies also suggest active infection (primary or reactivated). Because of the high seroprevalence of HHV-6 in the general population, a single positive HHV-6 or -7 IgG test is of no diagnostic significance for diagnosis of acute infection. CMV antibodies can cross react with HHV-6 and HHV-7; therefore, diagnosis of HHV-6 and HHV-7 infections by serologic means requires exclusion of CMV infection.
Identification of HHV-6 or HHV-7 in PBMCs by virus culture firmly establishes the presence of active infection in immunocompetent hosts; association with specific disease is more problematic in immunocompromised patients as a result of a low background rate of viremia. Identification of HHV-6 and HHV-7 by culture requires incubation of PBMCs (with or without co-cultivation with exogenous PBMCs) for days to several weeks, and is presently available only in research laboratories. A commercial HHV-6 rapid (shell-vial) culture is available; it appears comparable to standard virus culture for detection of active HHV-6 infection.
PCR amplification tests for HHV-6 are becoming available and may provide more timely information for diagnosis. Active, replicating infection is indicated if HHV-6 DNA is detected in acellular specimens such as serum or cerebrospinal fluid. However, detection at other sites (e.g., PBMCs, saliva, and tissues) does not necessarily indicate active infection, because HHV-6 exists in latent form in many tissues after primary infection.
Other diagnostic tests for consideration in selected circumstances include in situ hybridization and immunohistochemistry.
White blood cell (WBC) counts of 8,000–9,000?WBCs/µL may be found during the first few days of fever in children with roseola, but by the time the exanthem appears, the WBC count falls to 4,000–6,000?WBCs/µL with a relative lymphocytosis (70–90%). The cerebrospinal fluid in children with HHV-6–associated febrile seizures typically is normal. The cerebrospinal fluid from rare cases of HHV-6–associated meningoencephalitis and encephalitis is characterized by a mild pleocytosis with predominance of mononuclear cells, normal glucose, and normal to slightly elevated protein.
Children with roseola typically present at two different stages of the illness: at the time of fever before the rash (pre-eruptive) and after the rash has appeared. During the pre-eruptive stage, many conditions may be confused with roseola. However, the pattern of fever in a generally well child without significant physical findings, rather precipitous defervescence, and a subsequent rash is unique for roseola. Nonetheless, some patients may not display all these characteristics and conditions may mimic other illnesses.
Roseola is probably most commonly confused with rubella. In contrast to the absence of a distinct prodrome in children with roseola, children with rubella invariably have a mildly symptomatic prodromal period, including prominent occipital and postauricular lymphadenopathy. Lymphadenopathy is an inconsistent finding in roseola; when lymphadenopathy does occur, occipital lymph nodes are more frequently affected than those in the postauricular region. Rubella usually causes only low-grade fever, which is coincident with the exanthem. The rubella rash is typically more extensive than that seen with roseola, and coalescence is more common. A history of exposure is frequently elicited from those in whom rubella develops. Most important, vaccinated persons rarely acquire rubella.
Roseola may be confused with measles. However, the development of an exanthem at the height of the fever, as well as the presence of cough, coryza, conjunctivitis, and Koplik spots on the buccal mucosa in the early stages of measles, differentiates these two illnesses.
Outbreaks of roseola-like illnesses have been associated with many different viruses, most commonly enteroviruses. In summer and fall months, some cases of roseola-like illnesses may be attributable to enteroviruses.
Scarlet fever may also resemble roseola. Important features of scarlet fever are its rarity in infancy, the simultaneous presence of fever and rash, and the discrete, small, sandpaper-like rash lesions.
Drug hypersensitivity is a common condition resembling roseola. Antibiotics are frequently prescribed to children with roseola during the febrile phase before onset of the rash. A child who acquires a drug rash may do so soon after resolution of the fever, which is the characteristic pattern for children with roseola. However, the usually morbilliform nature, pruritus, and resolution after discontinuation of the implicated drug should distinguish a drug rash.
It may be difficult to distinguish central nervous system disease caused by HHV-6 from other causes. Development of a roseola-like illness in association with febrile seizures, meningoencephalitis, or encephalitis makes HHV-6 infection more likely; however, this occurs infrequently.
Hepatitis and heterophile-negative mononucleosis are rarely associated with HHV-6, and other causes for these infections should first be sought.
HHV-6 is inhibited by ganciclovir, cidofovir, and foscarnet (but not acyclovir) at levels that are achievable in serum; HHV-7 is inhibited by cidofovir and foscarnet. Case reports have indicated successes and failures with these drugs; however, prospective trials evaluating the clinical efficacy of antiviral agents for HHV-6 or HHV-7 infections have not been performed.
The generally benign nature of roseola precludes consideration of antiviral therapy. However, future studies may address the need for specific antiviral therapy in those unusual cases of roseola or other forms of HHV-6 infection in which significant morbidity exists, such as children with neurologic complications of roseola or immunocompromised children with severe HHV-6 or HHV-7 infection.
Children in the febrile, pre-eruptive phase of roseola usually are quite comfortable and require little supportive therapy. Those children who are uncomfortable and irritable, or in whom histories of febrile convulsions exists, may benefit from treatment with acetaminophen or ibuprofen. Adequate fluid balance should be maintained in all affected children. Referral should be considered in those unusual circumstances in which serious disease develops, such as encephalitis, hepatitis, or pneumonitis.
The prognosis for the great majority of children with roseola is excellent, with no obvious sequelae. Before the discoveries of HHV-6 and HHV-7, rare complications of roseola (hemiparesis, mental retardation) were attributable to brain anoxia during prolonged febrile seizures. However, damage resulting from direct viral invasion of the brain, liver, and other organs has been demonstrated for HHV-6. Deaths directly attributable to HHV-6 have been reported in normal as well as immunocompromised patients in whom encephalitis, hepatitis, pneumonitis, disseminated disease, or hemophagocytosis syndrome developed.
Very little information is available on which to base guidelines for prevention of HHV-6 or HHV-7 infection. Experimental evidence suggests that roseola may be transmitted via blood or saliva, and both HHV-6 and HHV-7 are shed in the saliva. It is likely that healthy immune carriers with latent viral infections transmit infection to susceptible infants and children. No specific recommendations for prevention can be made until proper studies have been conducted. No vaccine has been developed.