Roseola Infantum (Exanthema Subitum, Sixth Disease)


Article Author:
Tessa Mullins


Article Editor:
Karthik Krishnamurthy


Editors In Chief:
Chaddie Doerr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/10/2019 8:24:32 AM

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.


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Roseola Infantum (Exanthema Subitum, Sixth Disease) - Questions

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A 2-year-old child presents with numerous skin lesions on his arm and trunk. Two months prior, he received chemotherapy for a neuroblastoma. The lesions are non-tender, nonpruritic, and bright red. Biopsy reveals an inclusion body in the nucleus of the cells. What is the most likely cause?



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Which of the following most likely causes high fever, maculopapular rash starting after the fever resolves, conjunctivitis, upper respiratory symptoms, and a bulging fontanelle?



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A 2-year-old child is seen in the dermatology clinic with numerous skin lesions on his arm and trunk. Two months prior, he had received chemotherapy for a neuroblastoma. The lesions are bright red, non-tender, and non- itchy. Biopsy reveals an inclusion body in the nucleus of the cells. What is the most likely cause?



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Which of the following infections typically presents with a prodromal febrile illness lasting several days followed by a defervescence and the appearance of a faint pink rash?



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What is the most common symptom an infant with roseola infantum?



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What is the second most common symptom of roseola infantum?



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What percentage of patients with roseola infantum are at risk for seizures?



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What group contains the organism that causes roseola infantum?



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What is the most likely cause of high-grade fever followed by a generalized skin rash in a child?

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What is the cause of exanthema subitum?



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A 12-month-old female has several days of high fever, but no source is found. A maculopapular, erythematous, evanescent, generalized rash develops. What is the most likely etiology?



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An infant aged 6 months has had a high fever for several days, with non-specific viral symptoms. Now well, he presents with a pale pink rash that blanches. What is the likely cause of his illness?



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Which subtype of human herpesvirus 6 is most likely to cause roseola infantum?



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An 18-month-old child presents to the clinic complaining of a fever. The mother at bedside reports that one week ago her daughter developed nonpruritic, erythematous papules distributed over her trunk but the rash has since resolved. On exam, her son appears well except for a fever of 101.4 F. All other clinical exam findings are normal. The mother is very concerned about the possibility of a serious infection. Which of the following is the next best step in the management of this patient?



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A 5-year-old female with a past medical history of atopic dermatitis, asthma, and osteosarcoma that is admitted to the hospital is being evaluated for a fever of unknown origin. The patient is currently undergoing chemotherapy for her osteosarcoma but otherwise has no other complaints. She reports taking an albuterol inhaler as needed for asthma attacks and uses a ceramide lotion for her atopic dermatitis per mother at the bedside. On physical exam, her vitals are within normal limits except a temperature of 102.1 F. Physical exam is otherwise unremarkable. Lab work is ordered. Two days later, the patient develops an asymptomatic, pink papular rash located on her trunk and extremities. However, the fever has resolved. Upon further investigation, it is discovered that the patient had a similar rash three years ago. What is the most likely explanation for the child's rash?



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A 3-year-old otherwise healthy male presents to the clinic with complaints of a new rash. His father at bedside reports the rash began suddenly one day ago after a high fever that lasted four days. Physical exam shows 1-2 mm, pink papules distributed over the child's trunk. The child appears well. It is explained to the father that the rash is most likely caused by a virus. Which of the following viruses is most closely related to the causative infectious agent?



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A4-year-old otherwise healthy female presents to the emergency department for evaluation after her mother witnessed a seizure at home. Mother reports the patient has had a fever above 102 F for the past three days. She has no past medical history and no family history of seizures. Mother denies any trauma, prodrome, or other systemic complaints. During the examination, the child appears irritable. Vital signs demonstrate a fever of 101.3 F. The rest of the physical exam is unremarkable. Imaging and lab work are within normal limits. Acetaminophen is advised for the fever. Two days later, the mother calls to inform the office that the patient's fever has subsided but that he has developed 1-2 mm pink papules distributed over his trunk that are progressing to his extremities. Which of the following best explains the seizures in this child?



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A 5-year-old child with a past medical history of preterm birth and chronic infections presents to the clinic with his grandmother. She states that the child developed a fever of 103 F three days ago with defervescence of the fever last night. The child woke up with erythematous papules located on his trunk, extremities, and neck. Grandmother states the lesions do not appear to bother the child, and he has been acting normally at home. She states, "he is always sick." The child has taken no medications, and no other family members have the rash. What is the best course of treatment for this patient?



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Roseola Infantum (Exanthema Subitum, Sixth Disease) - References

References

De Bolle L,Naesens L,De Clercq E, Update on human herpesvirus 6 biology, clinical features, and therapy. Clinical microbiology reviews. 2005 Jan;     [PubMed]
Agut H,Bonnafous P,Gautheret-Dejean A, Laboratory and clinical aspects of human herpesvirus 6 infections. Clinical microbiology reviews. 2015 Apr     [PubMed]
Tesini BL,Epstein LG,Caserta MT, Clinical impact of primary infection with roseoloviruses. Current opinion in virology. 2014 Dec     [PubMed]
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]
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