Review summarizes experience from Japan and U.S.
The first disease clearly associated with primary HHV-6 infection was exanthem subitum (ES), also called roseola (Yamanishi 1988). When this report was published, some investigators concluded that HHV-6 caused ES, and no other disease. Since then, however, clinical manifestations of primary HHV-6 infection in young children has been increasingly recognized as common. Moreover, primary HHV-6 infection sometimes causes serious illness. Investigators from Aishi, Japan, have written an excellent review of the diseases caused by primary infection with HHV-6 in children.
ES is typically described as a “benign childhood disorder” and, indeed, it is usually self-limited. It begins with a high-grade fever that lasts for 2–4 days. Children often are described as more irritable than they have been with other illnesses that have produced fevers of similar magnitude. Occasionally, children with ES have edematous eyelids, cervical lymphadenopathy, uvulo-palatoglossal junctional macules or ulcers (Nagayama spots), diarrhea, and a bulging fontanelle. Otherwise, the children often are well appearing and alert. When the fever subsides, a maculopapular rash appears. The rash starts on the neck and trunk, and spreads to the face and extremities. Usually, it is not itchy, and lasts for just 3–4 days.
On very unusual occasions, however, ES can be complicated by hepatitis, hemophagocytic syndrome, myocarditis, and central nervous system (CNS) diseases including febrile seizures (FS), febrile status epilepticus (FSE) and encephalitis. Supporting a likely role of HHV-6 in causing these complications of ES, each of the complications also has been linked to HHV-6 in children who do not manifest the full syndrome of ES.
Studies from Japan have found that ES occurs in 90% of children who are under 2 years of age, but in only 50% of children older than 2 years of age, when they experience a primary HHV-6B infection. Studies in the U.S. have found that primary HHV-6 infection most often does not cause full-blown ES, but more often causes just fever, a rash, or FS.
In Japan, FS appears to be the main reason for patients with primary HHV-6B infection to visit the emergency room. A large survey in Japan found that HHV-6B was responsible for 12% of emergency room visits in children with fever under 6 years of age. Large studies in the U.S. have found that HHV-6 is responsible for 9.7–18% of febrile infants and children younger than 3 years of age who visited ERs in the USA.
A recent meta-analysis found that FS were caused by HHV-6 infection in 21% of cases. In addition, the two most common causes of acute encephalopathy in young children were found to be influenza virus and HHV-6B.
Interestingly, data from Japan found that the incidence of ES, and of other manifestations of primary HHV-6 infection, did not drop during the COVID-19 pandemic in the way that the incidence of many other viral diseases did. That is probably because most cases of primary HHV-6 infection begin following horizontal infection from very close contact with a family member, including sharing food containing saliva.
Another interesting observation cited in the review is that, at least in Japan, today the median age at the time of infection is 15 months, which is significantly older than it was several decades earlier.
This review is a concise summary of interesting clinical and epidemiological data about primary HHV-6 infection in very young children, in Japan and elsewhere.
Read the full text: Kawamura 2024