ROSEOLA

Jeffrey D. Quinlan, MD, FAAFP

 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 posttransplant (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

 DIAGNOSIS

HISTORY

•  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 (5)

•  Mild upper respiratory symptoms (5)

•  Rhinorrhea (5)

•  Febrile seizure occurs in 13% of cases (1).

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

 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].

 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).

COMPLICATIONS

•  Febrile seizures

–  13% patients with roseola (1,6)

–  Accounts for 1/3 of primary seizures in children <2 years old (1)

•  Medication hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms) (4)

•  Reactivation can occur in transplant patients, HIV-1 infection, and other immunocompromised individuals (6).

•  Meningoencephalitis occurs in immunocompetent and in immunosuppressed patients (6). Poor association with multiple sclerosis (6)

•  Pityriasis rosea (1)

•  Possible association with progressive multifocal leukoencephalopathy (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 herpesrviruses 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 herpesrvirus 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

•  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

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

•  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.