Roseola Infantum (Exanthema Subitum, Sixth Disease)

Article Author:
Tessa Mullins
Article Editor:
Karthik Krishnamurthy
Updated:
6/10/2019 8:24:32 AM
PubMed Link:
Roseola Infantum (Exanthema Subitum, Sixth Disease)

Introduction

Roseola infantum is a common disease of childhood caused by a primary infection with human herpesvirus 6 (HHV-6) and less frequently, by human herpesvirus 7 (HHV-7). This disease, also known as exanthema subitum and sixth disease, presents in children ages six to 12 months with 90% of cases occurring in children younger than two years. Caused by the B variant of HHV-6, patients with the virus classically present with an acute onset of a high-grade fever up to 40 C (104 F) for three to five days. The child will experience a rapid defervescence of the fever with accompanying nonpruritic, pink papular rash that begins on the trunk. It is found universally and has been discovered to be the cause of 10% to 45% of febrile illness in infants. Due to the high fever and the ability of the virus to cross the blood-brain barrier, 15% of children will also experience an acute febrile seizure during the febrile phase of the illness.  Roseola infantum is a clinically diagnosed, self-limited illness that can be treated symptomatically. HHV-6 will likely remain latent in immunocompetent patients but can be a major cause of morbidity and mortality in patients who are immunosuppressed. 

Etiology

Human herpesvirus 6, a virus found in the Herpesviridae family, causes roseola infantum. HHV-6 is a betaherpesvirus, closely related to human cytomegalovirus (HCMV) and human herpesvirus 7 (HHV-7)[1]. This group of betaherpesvirus is known to have less cell tropism than other members of the Herpesviridae family. HHV-6 contains a linear, double-stranded DNA genome and is flanked by direct terminal repeats that contain reiterations of a hexanucleotide, GGGTTA. These reiterations have been thought to play a role in the maintenance of the viral genome in latently infected cells[2].

Epidemiology

Human herpesvirus 6 has been found to be the cause of febrile illness in 10% to 45% of infants in the United States. A 2005 population-based study indicated that 40% of HHV-6 infection is seen by age twelve months and 77% is seen by age 24 months[3]. This study also reported that the virus is seen in both males and females, but was more common in females and children with older siblings. The peak incidence of the virus is in the spring and fall seasons. Transmission occurs primarily through saliva via respiratory droplets[3].

Pathophysiology

Human herpesvirus 6 replicates most commonly in the leukocytes and the salivary glands during the primary infection and will, therefore, be present in saliva. Research has shown that 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[4]. Early invasion of the central nervous system (CNS) has also been shown[5].

Roseola infantum is most commonly caused by human herpesvirus 6 and less commonly, human herpesvirus 7. Human herpesvirus 6 has two variants: A and B. The primary variant that causes roseola infantum is HHV-6B. HHV-6A has not yet been linked to any disease. Both variants enter the cell via interaction with CD46[2] HHV-6B is involved in the fusion process to the cell membrane by an undefined mechanism, the nucleocapsid is transported through the cytoplasm, and the viral DNA genome is released into the nucleoplasm at nuclear pore complexes. It has been shown that HHV-6 replicates most effectively in CD4+ T cells and has a mean incubation period of nine to ten days[1].

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[6].

History and Physical

Classic roseola infantum is a clinically based diagnosis. It begins with a high fever that may exceed 40 C (104 F). The fever typically lasts three to five days. During the fever, children may appear to be active and well. However, children may also have malaise, conjunctivitis, orbital edema, inflammation of the tympanic membranes, lymphadenopathy, irritability, anorexia, a bulging fontanelle, diarrhea, cough and other upper respiratory tract symptoms. Uvulopalatoglossal spots also referred to as Nagayama spots, are erythematous papules found on the soft palate and uvula that are seen in two-thirds of patients[3].

Upon rapid defervescence of the fever around days three to five, small, rose-pink or red 2 mm to 5mm papules and macules will develop. A pale halo can occur around the macules and papules in some cases. The rash usually begins on the trunk and can spread to the neck, extremities, and face. The rash is typically nonpruritic, blanching and can persist from one to two days[7].

Evaluation

Laboratory tests are unlikely to be necessary for the evaluation of roseola infantum but are sometimes drawn during the febrile phase of the illness to rule out other diagnoses. Children infected with HHV-6 can have an elevated white blood cell count that will gradually return to normal over a period of seven to ten days following the illness. A retrospective study at a single institution in 2013 reported that some children might have sterile pyuria during an active infection with HHV-6[8].

Treatment / Management

There is no specific treatment for roseola infantum. The majority of cases of roseola infantum are mild and self-limited. Treatment is supportive with rest, maintaining fluid intake and antipyretics such as acetaminophen or ibuprofen to control the fever. Due to the rash likely being nonpruritic, treatment is unnecessary[7]. There is currently no vaccination or antiviral therapy for the acute phase of this virus. Adequate hand washing is very important to prevent the spread of the disease.

Differential Diagnosis

Measles

Rubella

Scarlet fever

Viral exanthem

Exanthematous drug eruption

Prognosis

The prognosis of roseola infantum is excellent. It is a self-limited disease with few long term adverse events. 

Complications

Primary HHV-6 infection has been associated with a large range of potential complications including myocarditis, rhabdomyolysis, thrombocytopenia, Guillain-Barre syndrome and hepatitis. The presence of HHV-6 DNA in the target organ, PBMCs, or other body fluids as evidence of active HHV-6 infection have been used by many case reports and small case studies[3]

Deterrence and Patient Education

While roseola infantum is a self limited viral condition, is important to follow up with a board certified health care provider if your child has a high fever. 

Pearls and Other Issues

The most likely complication from infection with HHV-6 is febrile seizures. Up to 15% of children will experience seizures during their illness due to the high fevers and ability of the virus to enter the blood-brain barrier. Signs of a febrile seizure include and are not limited to: loss of consciousness, twitching or jerking movements of the extremities, soiled clothing in a potty trained child, and irritability.

Reactivation of the virus can occur in immunosuppressed patients. Children with cancer and recipients of transplants are at increased risk of reactivation. A 2003 university study of children with hematopoietic cells transplants and solid organ transplants reported approximately 50% and 20% to 30% reactivation of HHV-6, respectively[9]. Bone marrow failure, meningoencephalitis, myocarditis, pneumonitis and hepatitis can occur. In these more severe cases, the illness can be treated with ganciclovir or foscarnet antivirals[2].

Enhancing Healthcare Team Outcomes

Roseola infantum is managed by a multidisciplinary team that includes pediatric nurses. The condition is benign and resolves spontaneously. However, a few children may develop febrile seizures. Rarely in immunocompromised children, the infection may recur.

Most children have no residual sequelae and have an excellent prognosis.


References

[1] De Bolle L,Naesens L,De Clercq E, Update on human herpesvirus 6 biology, clinical features, and therapy. Clinical microbiology reviews. 2005 Jan;     [PubMed PMID: 15653828]
[2] Agut H,Bonnafous P,Gautheret-Dejean A, Laboratory and clinical aspects of human herpesvirus 6 infections. Clinical microbiology reviews. 2015 Apr     [PubMed PMID: 25762531]
[3] Tesini BL,Epstein LG,Caserta MT, Clinical impact of primary infection with roseoloviruses. Current opinion in virology. 2014 Dec     [PubMed PMID: 25462439]
[4] Kittaka S,Hasegawa S,Ito Y,Ohbuchi N,Suzuki E,Kawano S,Aoki Y,Nakatsuka K,Kudo K,Wakiguchi H,Kajimoto M,Matsushige T,Ichiyama T, Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6-infected infants with or without febrile seizures. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2014 Nov     [PubMed PMID: 25156011]
[5]     [PubMed PMID: 28104930]
[6]     [PubMed PMID: 19496184]
[7]     [PubMed PMID: 24673253]
[8]     [PubMed PMID: 27980872]
[9]     [PubMed PMID: 22641196]