Roseola and herpes 6 and 7 infections

OVERVIEW: What every practitioner needs to know

Roseola, or exanthem subitum, is caused by the DNA virus human herpesvirus type 6 (HHV-6). HHV-6 commonly causes a febrile illness in young children between the ages of 5 to 18 months. The fevers often reach 39-40 degrees Celsius. The characteristic feature of roseola is the appearance of an exanthem when the fever abates around day 4-5 of illness. The erythematous rash can be macular, papular, or maculopapular; hence, the name roseola. The rash often appears first on the face and then spreads to the trunk. There is no desquamation when the exanthem fades. Less common features of roseola include diarrhea and febrile convulsions. HHV-6 strains are divided into A and B species. Most clinical cases of roseola are caused by the B species.

HHV-7 infection is less virulent than HHV-6 infection. Although HHV-7 rarely causes symptomatic disease, on occasion, infection can resemble roseola.

Are you sure your patient has roseola? What are the typical findings for this disease?

The sequential appearance of high fever followed by a maculopapular rash when the fever abates are the characteristic features of roseola in healthy children. Since most children acquire HHV-6 and HHV-7 infections by age 18 months, primary infection in immunocompromised children is rare. However, reactivation of these two viruses occurs commonly after immunosuppression following bone marrow and solid organ transplantation in children. In most cases, reactivation is characterized mainly by a febrile illness with detectable viremia. In a small number of cases, especially after liver transplantation, reactivation by HHV-6 may be associated with hepatitis in the transplanted liver. HHV-6 infection also has been associated with graft rejection after liver transplantation.

Key symptoms of roseola:

1. High fever

2. Maculopapular rash

What other disease/condition shares some of these symptoms?

Any virus infection that causes a rash can lead to confusion with roseola. These viruses include numerous enteroviruses as well as parvovirus. However, with these viral illnesses, the onset of fever and rash generally occur at the same time. Roseola can be confused with either measles or rubella in countries lacking immunization of children for the latter two diseases.

What caused this disease to develop at this time?

Roseola is caused by HHV-6. Most children with roseola are between 5 and 18 months of age. The mode of transmission is still not completely understood. The most likely method is by transmission in saliva after asymptomatic reactivation in a parent or sibling. In countries such as Japan, where multigenerational families more commonly live in the same household, grandparents may be a source of infection to their grandchildren. In the temperate climate zone, the infection is most common during the spring months of the year. There is one additional mode of transmission, namely, intrauterine spread from a seropositive mother. Congenital infections, which occur in approximately 1% of pregnancies, are asymptomatic in the newborn infant.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

HHV-6 infection is usually diagnosed by one of two methods. The first is polymerase chain reaction (PCR) amplification of viral DNA from peripheral blood cells. The second is serological testing for HHV-6 specific IgM antibody or a 4-fold rise of IgG specific antibody in two serum samples drawn at least 4 weeks apart.

Would imaging studies be helpful? If so, which ones?

For a typical case of roseola, imaging is not indicated. However, a small percentage of infants with HHV-6 will manifest seizures. Some seizures are febrile convulsions, whereas others reflect true HHV-6 meningoencephalitis. Therefore, in infants with central nervous system complications, magnetic resonance imaging (MRI) may be indicated to assess the extent of viral infection in the brain.

If you are able to confirm that the patient has roseola, what treatment should be initiated?

Roseola is a virus infection that is nearly always limited by an immune response in the otherwise healthy infant. For infants with severe meningoencephalitis in the presence of a documented acute HHV-6 infection, treatment with intravenous ganciclovir should be considered. The usual dosage of ganciclovir is 10 mg/kg/day, but some experts have treated HHV-6 encephalitis with a higher dosage of 18 mg/kg/day. Duration of treatment has ranged from 7-10 days. Since this antiviral medication is not approved for this indication in children, consultation with an infectious disease specialist should be considered before a final decision is made. Of note, acyclovir is not efficacious against HHV-6 infection.

What are the adverse effects associated with each treatment option?

Ganciclovir treatment can lead to serious side effects. Ganciclovir can cause bone marrow suppression and renal damage. Therefore, the use of this antiviral medication should be restricted to the most serious HHV-6 infections, especially those involving the central nervous system of otherwise healthy children. White blood cell counts and serum creatinine levels should be monitored during the entire course of treatment.

What are the possible outcomes of roseola?

The vast majority of infants with roseola recover with no sequelae. Even those who develop febrile convulsions will usually recover completely. In the United States, permanent sequelae occur in only a small number of infants with meningoencephalitis caused by HHV-6 infection; many of these complications occur in immunocompromised children. Of note, severe and even fatal HHV-6 encephalitis of healthy young children appears to be a more common illness in Japan.

What causes this disease and how frequent is it?

Roseola (exanthem subitum) is caused by infection with HHV-6, a DNA virus related to human cytomegalovirus. HHV-7 is closely related to HHV-6 at a genetic level.

How do these pathogens/genes/exposures cause the disease?

The mechanism of spread remains to be determined with certainty. What is known is that the infection spreads mainly to infants during the second half of their first year of life, likely from asymptomatic shedding of close household contacts. Symptomatic infections do occur in children ages two through four years. The male to female ratio is nearly equal.

Other clinical manifestations that might help with diagnosis and management

Most infants who contract HHV-6 infection develop too few symptoms to be diagnosed. Some studies estimate that only about 20% of infants with acute HHV-6 infection have clinically apparent roseola. Therefore, the majority of young children will be seropositive by the time they reach age four years.

What complications might you expect from the disease or treatment of the disease?

The major complication that occurs in otherwise healthy children who contract roseola is a bout of febrile seizures. HHV-6 infection is associated with one-third of all cases of prolonged febrile seizures in childhood. However, the prognosis is excellent in that the seizure episode does not portend an underlying seizure disorder in future years. In immunocompromised children, a reactivation occasionally leads to complications such as hepatitis and encephalitis, either of which can be severe.

Are additional laboratory studies available; even some that are not widely available?

In a small number of children infected with HHV-6, the viral genome is integrated into a human chromosome. Integration is particularly common after HHV-6 intrauterine infection. Diagnosis of integrated HHV-6 DNA requires fluorescent in situ hybridization technology with HHV-6 specific probes.

How can roseola be prevented?

There is no available means of preventing HHV-6 or HHV-7 infection; therefore, roseola cannot be prevented. There is no available vaccine.

What is the evidence?

Hall, CB, Long, CE, Schnabel, KC. “Human herpesvirus-6 infection in children. A prospective study of complications and reactivation”. N Engl J Med. vol. 331. 1994. pp. 432-8.

Hall, CB, Caserta, MT, Schnabel, KC. “Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7)”. J Pediatr. vol. 145. 2004. pp. 472-7.

Yoshikawa, T, Ohashi, M, Miyake, F. “Exanthem subitum-associated encephalitis: nationwide survey in Japan”. Pediatr Neurol. vol. 41. 2009. pp. 353-8.

Epstein, LG, Shinnar, S, Hesdorffer, DC. “Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study”. Epilepsia. vol. 53. 2012. pp. 1481-8.

Ongoing controversies regarding etiology, diagnosis, treatment

As noted above, HHV-6 reactivation occurs commonly in children following bone marrow or organ transplantation. However, in most of these patients, reactivations of other herpesviruses, such as cytomegalovirus and Epstein-Barr virus, are also detected. In situations where pneumonia or encephalitis develop after transplantation, HHV-6 is more likely to be considered a co-pathogen and not the major pathogen. However, if after an extensive diagnostic evaluation, only HHV-6 reactivation is detected, treatment with ganciclovir can be considered.