para>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 ¢ … “; 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
11 Stone ‚ RC, Micali ‚ GA, Schwartz ‚ RA. Roseola infantum and its causal human herpesviruses. Int J Dermatol. 2014;53(4):397 " “403.22 Watkins ‚ J. Diagnosing rashes, part 4: generalized rashes with fever. Practice Nursing. 2013;24:335 " “340.33 Ely ‚ JW, Seabury Stone ‚ M. The generalized rash: part I. Differential diagnosis. Am Fam Physician. 2010;81(6):726 " “734.44 Wolz ‚ MM, Sciallis ‚ GF, Pittelkow ‚ MR. Human herpesrviruses 6, 7, and 8 from a dermatologic perspective. Mayo Clin Proc. 2012;87(10):1004 " “1014.55 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 " “776.66 Caserta ‚ MT, Mock ‚ DJ, Dewhurst ‚ S. Human herpesrvirus 6. Clin Infect Dis. 2001;33(6):829 " “833.77 Le ‚ J, Gantt ‚ S. Human herpesvirus 6, 7 and 8 in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):128 " “137.88 Ely ‚ JW, Seabury Stone ‚ M. The generalized rash: part II. Diagnostic approach. Am Fam Physician. 2010;81(6):735 " “739.99 Dreyfus ‚ DH. Herpesviruses and the microbiome. J Allergy Clin Immunol. 2013;132(6):1278 " “1286.1010 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.
- F ƒ ¶lster-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
- B09 Unsp viral infection with skin and mucous membrane lesions
ICD9
- 058.10 Roseola infantum, unspecified
- 058.11 Roseola infantum due to human herpesvirus 6
- 058.12 Roseola infantum due to human herpesvirus 7
- 057.8 Other specified viral exanthemata
SNOMED
- 54385001 Exanthema subitum
- 402902002 Roseola infantum (HHV 6)
- 402903007 Roseola infantum (HHV 7)
- 402419007 Roseolar erythema
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.