Internal Medicine

Roseola infantum

Roseola infantum or exanthem subitum or Sixth disease is a common childhood exanthematous illness caused by primary infection primarily by human herpesvirus (HHV)-6 and less commonly by HHV-7 and echovirus 16.

Common childhood exanthematous illness caused primarily by human herpesvirus (HHV)-6 and less commonly by HHV-7 and echovirus 16.

  • Also known as exanthema subitum or Sixth disease
  • Responsible for 10-45% of febrile illness in infants


The syndrome known as roseola infantum was reported as early as 1809 by Robert Willan in his textbook “On cutaneous diseases”. This clinical entity is also commonly referred to as exanthem subitum and early published descriptions of the disease still hold true. It is an illness that affects children by the age of three and is marked by the abrupt development of high fever lasting 3-5 days. The hallmark maculopapular rash appears as the fever subsides, and there may be few, if any, associated symptoms. Despite knowledge of this common disease of infancy, the etiologic agent was not identified until 1988 by Yaminishi and colleagues. They demonstrated both the presence of circulating virus in peripheral blood mononuclear cells (PBMCs) during acute roseola and subsequent seroconversion during convalescence in four infants in Japan. It was nearly a decade later before our understanding of the full clinical spectrum of HHV-6 primary infection was expanded past roseola.


  • Human herpesvirus 6 (HHV)-6 (M/C)
  • Less commonly,
    • HHV-7
    • Echovirus 16
An electron micrograph of HHV-6 also includes a labelled insert of the mature virus particle. The HHV-6 is a double stranded DNA virus of the herpes family. The virus particles shown here have matured and are then released from the lymphocyte which has been infected. The “owl’s eye” appearance of the virus particles is characteristic of the herpes family. The HHV-6, or the human herpes virus-6, was thought to infect b-cells and was at one time called HBLV, human b-lymphotropic virus. It is now known to infect t-cells and is the cause of the childhood rash “roseola” and some cases of mononucleosis. | Topics/Categories Cells or Tissue, Abnormal Cells or Tissue Type Color, Photo Source Laboratory Of Tumor Cell Biology

HHV6 replicates most commonly in the leukocytes and the salivary glands during the primary infection and will, therefore, be present in saliva. High levels of metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 in the serum of infants infected with HHV-6 can lead to blood-brain barrier dysfunction which in return can aid in causing febrile seizures.

HHV-6 remains latent in lymphocytes and monocytes after an acute primary infection with the salivary glands and brain tissue harboring persistent HHV-6 infection.

Clinical features

Presents in children 6-12 months with 90% of cases occurring in children younger than 2 years


Mild upper respiratory signs
  • Rhinorrhea
  • Pharyngeal inflammation
  • Conjunctival redness
  • Mild cervical or occipital lymphadenopathy
  • Palpebral oedema (sometimes)

Febrile phase:

  • Acute onset of high-grade fever (up to 40°C/104°F) for 3-5 days
  • Nagayama spots (uvulopalatoglossal spots) (⅔ cases): Erythematous papules found on soft palate and uvula
  • Associated febrile seizures (15% cases): Due to the high fever and the ability of the virus to cross the blood-brain barrier

Hallmark maculopapular rash

Rapid defervescence of fever with accompanying nonpruritic, pink papular rash that begins on the trunk within 12-24 hr
  • Discrete erythematous and maculopapular
  • Spread: Trunk → Face, neck and proximal extremities
  • The rash is nonpruritic, rarely becomes confluent and fades in 3-4 days.
Roseola on a 21-month-old girl | M Davis – Public Domain,


  • Myocarditis
  • Rhabdomyolysis
  • Thrombocytopenia
  • Guillain-Barre syndrome
  • Hepatitis/fulminant hepatic failure



HHV-6 Antibody Titer in 0-36 Month Old Children and Acquisition of Primary Infection. | N Engl J Med, Hall CB et al., Human Herpesvirus-6 Infection in Children: A Prospective Study of Complication and Reactivation. 331: 432-8. Copyright (1994) Massachusetts Medical Society. Reprinted with permission.

Differential diagnosis:

The name “fifth disease” comes from its place on the standard list of rash-causing childhood diseases:
  1. Measles (first)
  2. Scarlet fever (second)
  3. Rubella (third)
  4. Dukes’ disease (fourth, but is no longer widely accepted as distinct)
  5. Erythema infectiosum (fifth)
  6. Roseola (sixth)
Classic Exanthems and Viral Rashes | Approach to the Pediatric Patient with a Rash | Clinical Gate. Retrieved February 05, 2021, from


Roseola infantum is a clinically diagnosed, self-limited illness that can be treated symptomatically.

Symptomatic management

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