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Roseola
Jeffrey D. Quinlan, MD, FAAFP
image BASICS
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
DESCRIPTION
  • 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 (2)
  • System(s) affected: skin/exocrine, metabolic, gastrointestinal, respiratory, neurologic
  • Synonym(s): roseola infantum, exanthem subitum; pseudorubella; sixth disease; 3-day fever (3)
Pediatric Considerations
A disease of infants and very young children (4)
EPIDEMIOLOGY
  • Predominant age
    • HHV-6
      • Infants and very young children (<2 years old) (5)
      • Peak age infection 6 to 9 months, rarely congenital or perinatal infection (1)
      • 95% of children have been infected with HHV-6 by 2 years of life.
    • HHV-7
      • Later childhood
      • Mean age of infection 26 months
      • >90% population with HHV-7 by 10 years (1)
  • Predominant sex: male = female (1)
  • No seasonal variance
Incidence
Common—accounts for 20% ED visits for febrile illness among children 6 to 8 months (6)
Prevalence
  • Peak prevalence is between 9 and 21 months (5).
  • Nearly 100% population carrying HHV-6 by 3 years (1)
  • Approximately 20% patients with primary HHV-6 have roseola (6).
ETIOLOGY AND PATHOPHYSIOLOGY
  • HHV-6 and HHV-7 (4)
  • Majority of cases (60-74%) due to HHV-6
    • HHV-6B > HHV-6A (4)
    • HHV-6A seen in children in Africa
    • HHV-6 binds to CD46 receptors on all nucleated cells (4).
  • 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).
    • 80-90% population intermittently sheds HHV-6/HHV-7 in saliva (4).
    • Patients are viremic from 2 days prior to fever until defervescence and onset of rash.
    • HHV-6 latency is also implicated in CSF (6).
Genetics
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).
RISK FACTORS
  • Female gender (5)
  • Having older siblings (5)
  • At-risk adults: immunocompromised (7)
    • Renal, liver, other solid organ, and bone marrow transplant (BMT) (5)
    • HHV-6 reactivation can occur in 1st week post-transplant (7). HHV-6 viremia occurs in 30-45% of BMT within the first several weeks after transplantation (6).
      • Usually asymptomatic (6)
      • Up to 82% of HHV-6 reactivation/reinfection in solid organ transplant (7)
  • Nonrisk factors (5)
    • Child care attendance
    • Method of delivery
    • Breastfeeding (HHV does not appear to pass through breast milk)
    • Maternal age
    • Season
image DIAGNOSIS
PHYSICAL EXAM
  • Rash (exanthem subitum) (1)
    • Rose-pink macules and/or papules that blanch
    • First appears on the trunk then peripherally
    • May occur up to 3 days after fever resolves (1)
    • Fades within 2 days
    • Occurs in approximately 20% of patients in the United States (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 (4)
DIFFERENTIAL DIAGNOSIS
  • Enterovirus infection (8)
  • Adenovirus infection (1)
  • Epstein-Barr virus
  • Fifth disease—parvovirus B19 (8)
  • Rubella (8)
  • Scarlet fever (8)
  • Drug eruption (1)
  • Measles (1)
DIAGNOSTIC TESTS & INTERPRETATION
  • Primarily a clinical diagnosis not requiring laboratory or radiologic testing (1)
  • Tests often cannot differentiate latent or active disease (9).
  • Specific diagnosis only necessary in severe cases, unclear diagnosis where more serious disease needs to be ruled out, or if considering antiviral therapy (1).
Initial Tests (lab, imaging)
  • HHV-6 and HHV-7 by PCR (1,7)
    • Serum, whole blood, CSF, or saliva
    • Becoming more widely available
  • 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 suggests primary infection.
  • Viral culture (7)
    • Rarely done
    • No clinical use (very time consuming)
  • Other laboratory findings (1)
    • Decreased total leukocytes, lymphocytes, and neutrophils
    • Elevated transaminases
    • Thrombocytopenia
Diagnostic Procedures/Other
  • Urine culture: to rule out UTI as source of fever (2)
  • Chest x-ray (CXR): if a child has respiratory symptoms
P.931

image TREATMENT
No treatment necessary, resolves without sequelae (1)[C].
GENERAL MEASURES
  • Symptomatic relief including antipyretics (1)[C]
  • Hydration (1)[C]
MEDICATION
First Line
  • No specific first-line treatment in immunocompetent hosts beyond supportive measures (4)[C]
    • Antivirals are not recommended in immunocompetent.
  • No approved antiviral treatment in immunocompromised (4).
  • Second-line IV ganciclovir, cidofovir, foscarnet tested in vitro studies in stem cell transplant patients
    • HHV-6B susceptible: ganciclovir and foscarnet (7)[C]
    • HHV-6A and HHV-7 are more resistant to ganciclovir (7).
  • Antivirals suggested in individual cases of encephalitis (associated with reactivation of HHV-6) (7)
  • In bone marrow and stem cell transplant recipients receiving immunosuppression, ganciclovir prophylaxis is effective in preventing reactivation of HHV-6 (10)[B].
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • During febrile prodrome, monitor for dehydration.
  • None after typical rash appears and fever resolves
  • Mean duration of illness is 6 days (6).
  • If febrile seizures occur, they will cease after fever subsides and will not likely recur (6).
  • Symptomatic reactivation in immunocompromised (1)
DIET
Encourage fluids.
PATIENT EDUCATION
  • 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.
PROGNOSIS
  • Course: acute, complete recovery without sequelae (1)
  • Reactivation in immunocompromised patients is common (6).
REFERENCES
1. Stone RC, Micali GA, Schwartz RA. Roseola infantum and its causal human herpesviruses. Int J Dermatol. 2014;53(4):397-403.
2. Watkins J. Diagnosing rashes, part 4: generalized rashes with fever. Practice Nursing. 2013;24: 335-340.
3. Ely JW, Seabury Stone M. The generalized rash: part I. Differential diagnosis. Am Fam Physician. 2010;81(6):726-734.
4. Wolz MM, Sciallis GF, Pittelkow MR. Human herpesviruses 6, 7, and 8 from a dermatologic perspective. Mayo Clin Proc. 2012;87(10):1004-1014.
5. 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.
6. Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis. 2001;33(6):829-833.
7. Le J, Gantt S. Human herpesvirus 6, 7 and 8 in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):128-137.
8. Ely JW, Seabury Stone M. The generalized rash: part II. Diagnostic approach. Am Fam Physician. 2010;81(6):735-739.
9. Dreyfus DH. Herpesviruses and the microbiome. J Allergy Clin Immunol. 2013;132(6):1278-1286.
10. 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.
Additional Reading
&NA;
  • 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.
  • 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.
  • Dockrell DH, Smith TF, Paya CV. Human herpesvirus 6. Mayo Clin Proc. 1999;74(2):163-170.
  • Dyer JA. Childhood viral exanthems. Pediatr Ann. 2007;36(1):21-29.
  • Evans CM, Kudesia G, McKendrick M. Management of herpesvirus infections. Int J Antimicrob Agents. 2013;42(2):119-128.
  • 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.
  • Huang CT, Lin LH. Differentiating roseola infantum with pyuria from urinary tract infection. Pediatr Int. 2013;55(2):214-218.
  • Leach CT. Human herpesvirus-6 and -7 infections in children: agents of roseola and other syndromes. Curr Opin Pediatr. 2000;12(3):269-274.
  • 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.
  • 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.
Codes
&NA;
ICD10
  • 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
Clinical Pearls
&NA;
  • 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.