Omnipresent infection occurring in infancy and childhood. Majority of cases are caused by human herpesvirus 6 (HHV-6); may be associated with other diseases including encephalitis
- Acute infection of infants or very young children (1)
- Causes a high fever followed by a skin eruption as the fever resolves (1)
- Transmission via contact with salivary secretions or respiratory droplet (1)
- Incubation period of 9 to 10 days (1)
- System(s) affected: skin/exocrine, metabolic, gastrointestinal, respiratory, neurologic
- Synonym(s): roseola infantum, exanthem subitum; pseudorubella; sixth disease; 3-day fever (1)
A disease of infants and very young children (2)
- Predominant age
- Predominant sex: male = female (1)
- No seasonal variance
Common—accounts for 20% ED visits for febrile illness among children 6 to 8 months (4)
Etiology and Pathophysiology
- HHV-6 and HHV-7 (2)
- Majority of cases (60–74%) due to HHV-6
- Primary infection typically through respiratory droplets or saliva
- Congenital infection/vertical transmission occurs in 1% of cases (1).
- Transplacental transmission
- Chromosomal integration (clinical significance unknown)
- Lifelong latent or persistent asymptomatic infection occurs after primary infection (1).
HHV-6 is integrated into the chromosomes of 0.2–3.0% of the population. This leads to vertical transmission of the virus. Clinical significance of this is unknown (1).
- Female gender (3)
- Having older siblings (3)
- At-risk adults: immunocompromised (5)
- Renal, liver, other solid organ, and bone marrow transplant (BMT) (3)
- HHV-6 reactivation can occur in 1st week posttransplant (5). HHV-6 viremia occurs in 30–45% of BMT within the first several weeks after transplantation (4).
- Nonrisk factors (3)
- Child care attendance
- Method of delivery
- Breastfeeding (HHV does not appear to pass through breast milk.)
- Maternal age
- 3 to 5 days abrupt fever 102.2–104.0°F (39–40°C) not associated with a rash (1)
- The child may be fussy during this prodrome (1,6).
- Sudden drop of fever associated with appearance of rash (1)
- Rash on trunk then spreads centrifugally mainly to neck, possibly also to peripheral extremities, and face
- Diarrhea (3)
- Mild upper respiratory symptoms (3)
- Rhinorrhea (3)
- Febrile seizure occurs in 13% of cases (1).
- Rash (exanthem subitum) (1)
- Mild inflammation of tympanic membrane, pharynx, and/or conjunctiva (1,6)
- Ulcers on soft palate and uvula (Nagayama spots) (1)
- Cervical lymphadenopathy (1)
- Periorbital edema (2)
Diagnostic Tests & Interpretation
- Primarily a clinical diagnosis not requiring laboratory or radiologic testing (1)[C]
- Tests often cannot differentiate latent or active disease (1)[C].
- Specific diagnosis only necessary in severe cases, unclear diagnosis where more serious disease needs to be ruled out, or if considering antiviral therapy (1)[C]
Initial Tests (lab, imaging)
- HHV-6 and HHV-7 by PCR (1,5)[C]
- Serum, whole blood, CSF, or saliva
- Becoming more widely available
- Not required in non-immunocompromised individuals
- HHV-6 IgM immunofluorescence (1)
- Diagnostic for acute infection
- Spike seen in 1st week of illness
- HHV-6 IgG immunofluorescence (1)
- Check at diagnosis and then 2 weeks later.
- Use with IgM to show primary infection.
- Negative initial test and rise on follow-up suggest primary infection.
- Viral culture (5)
- Rarely done
- No clinical use (very time-consuming)
- Other laboratory findings (1)
- Decreased total leukocytes, lymphocytes, and neutrophils
- Elevated transaminases
- Urine culture: to rule out UTI as source of fever (2)
- Chest x-ray (CXR): if a child has respiratory symptoms
- No specific first-line treatment in immunocompetent hosts beyond supportive measures (2)[C]
- Antivirals are not recommended in immunocompetent.
- No approved antiviral treatment in immunocompromised (2)[C]
- Second-line IV ganciclovir, cidofovir, foscarnet tested in vitro studies in stem cell transplant patients
- Antivirals suggested in individual cases of encephalitis (associated with reactivation of HHV-6) (5)
- In bone marrow and stem cell transplant recipients receiving immunosuppression, ganciclovir prophylaxis is effective in preventing reactivation of HHV-6 (6)[B].
Follow-up RecommendationsPatient Monitoring
- Parental reassurance that this is usually a benign, self-limited disease (1)
- There is no specific recommended period of exclusion from out-of-home care for affected children.
- Patient is viremic a few days prior to fever until time of defervescence and rash onset.
- Febrile seizures
- Medication hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms) (2)
- Reactivation can occur in transplant patients, HIV-1 infection, and other immunocompromised individuals (4).
- Meningoencephalitis occurs in immunocompetent and in immunosuppressed patients (4); poor association with multiple sclerosis (4)
- Pityriasis rosea (1)
- Possible association with progressive multifocal leukoencephalopathy (4)
- Ablashi DV, Devin CL, Yoshikawa T, et al. Review part 3: human herpesvirus-6 in multiple non-neurological diseases. J Med Virol. 2010;82(11):1903–1910. [PMID:20872717]
- Caselli E, Di Luca D. Molecular biology and clinical associations of roseoloviruses human herpesvirus 6 and human herpesvirus 7. New Microbiol. 2007;30(3):173–187. [PMID:17802896]
- Dockrell DH, Smith TF, Paya CV. Human herpesvirus 6. Mayo Clin Proc. 1999;74(2):163–170. [PMID:10069356]
- Dyer JA. Childhood viral exanthems. Pediatr Ann. 2007;36(1):21–29. [PMID:17269280]
- Evans CM, Kudesia G, McKendrick M. Management of herpesvirus infections. Int J Antimicrob Agents. 2013;42(2):119–128. [PMID:23820015]
- Fölster-Holst R, Kreth HW. Viral exanthems in childhood—infectious (direct) exanthems. Part 1: classic exanthems. J Dtsch Dermatol Ges. 2009;7(4):309–316. [PMID:18803578]
- Huang CT, Lin LH. Differentiating roseola infantum with pyuria from urinary tract infection. Pediatr Int. 2013;55(2):214–218. [PMID:23190314]
- Leach CT. Human herpesvirus-6 and -7 infections in children: agents of roseola and other syndromes. Curr Opin Pediatr. 2000;12(3):269–274. [PMID:10836165]
- Lowry M. Roseola infantum. Pract Nurse. 2013;43:40–42.
- Stoeckle MY. The spectrum of human herpesvirus 6 infection: from roseola infantum to adult disease. Annu Rev Med. 2000;51:423–430. [PMID:10774474]
- Vianna RA, de Oliveira SA, Camacho LA, et al. Role of human herpesvirus 6 infection in young Brazilian children with rash illnesses. Pediatr Infect Dis J. 2008;27(6):533–537. [PMID:8449066]
- B08.20 Exanthema subitum [sixth disease], unspecified
- B08.21 Exanthema subitum [sixth disease] due to human herpesvirus 6
- B08.22 Exanthema subitum [sixth disease] due to human herpesvirus 7
- B09 Unsp viral infection with skin and mucous membrane lesions
- 057.8 Other specified viral exanthemata
- 058.10 Roseola infantum, unspecified
- 058.11 Roseola infantum due to human herpesvirus 6
- 058.12 Roseola infantum due to human herpesvirus 7
- 402419007 Roseolar erythema
- 402902002 Roseola infantum (HHV 6)
- 402903007 Roseola infantum (HHV 7)
- 54385001 Exanthema subitum
- Roseola infection should be suspected if an infant or young child presents with a high temperature without other clinical findings.
- As the fever abates, a macular rash will be seen on the trunk, with eventual spread to the face and extremities in 20% of patients.
- Roseola is a clinical diagnosis, and laboratory testing is not necessary for most children with classic presentation.
- For atypical presentations, complications, and immunocompromised hosts, several laboratory tools are available, including serologic testing for antibody, viral PCR testing, and viral culture.
- Infection is typically self-limiting and without sequelae.
- Usually, only symptomatic treatment is needed.
- Consider prophylaxis in patients undergoing bone marrow or stem cell transplant and receiving immunosuppressive therapy.
Jeffrey D. Quinlan, MD, FAAFP
- Stone RC, Micali GA, Schwartz RA. Roseola infantum and its causal human herpesviruses. Int J Dermatol. 2014;53(4):397–403. [PMID:24673253]
- Wolz MM, Sciallis GF, Pittelkow MR. Human herpesviruses 6, 7, and 8 from a dermatologic perspective. Mayo Clin Proc. 2012;87(10):1004–1014. [PMID:22819486]
- Zerr DM, Meier AS, Selke SS, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. 2005;352(8):768–776. [PMID:15728809]
- Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis. 2001;33(6):829–833. [PMID:11512088]
- Le J, Gantt S; for AST Infectious Diseases Community of Practice. Human herpesvirus 6, 7 and 8 in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):128–137. [PMID:23465006]
- Tokimasa S, Hara J, Osugi Y, et al. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;29(7):595–598. [PMID:11979309]
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