Roseola infantum

Roseola infantum 

Updated 2010 Jul 15 02:21:00 PM: review of generalized rash (Am Fam Physician 2010 Mar 15)Show more updates

General Information Description: 

childhood infection associated with high fever and macular or maculopapular rash

Also called:     

exanthem subitum exanthema subitum roseola subitum roseola infantalis sixth disease

Who is most affected: 

infants and young children, usually < 3 years old

Incidence/Prevalence:   



common human herpes virus 6 (HHV-6) has been identified in populations worldwide primary HHV-6 infection accounted for 9.7% of emergency department visits for acute febrile illnesses in 1,653 children 2 weeks to 25 months old, 20% of 365 visits for children 6-12 months of age; HHV-6 infection accounted for 1/3 of all febrile seizures in children < 2 years old (N Engl J Med 1994 Aug 18;331(7):432) primary HHV-6 infection very common in children < 2 years old; prospective cohort of 277 children followed from birth through age 2 years, saliva tested weekly for HHV-6 DNA using polymerase chain reaction, parents maintained daily log of signs and symptoms of illness; primary HHV-6 infection occurred in 130 children (47%) but study limited by high dropout rates (median follow-up 60 weeks), cumulative incidence of primary HHV-6 infection 40% at age 12 months and 77% at age 24 months among subjects completing follow-up, peak age of acquisition between 9 and 21 months; among 81 children with well-defined time of HHV-6 acquisition, 93% had symptoms and 38% were seen by physician (N Engl J Med 2005 Feb 24;352(8):768), commentary can be found in Am Fam Physician 2005 Dec 1;72(11):2337

Causes and Risk Factors

Causes:  

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human herpes virus types 6 and 7; human herpes virus 6 identified in 1988 two strains of HHV-6 have been recognized - subtype A and B o HHV-6B was predominant strain in almost all studies o HHV-6A not consistently associated with a specific disease, more common in African American children review of human herpes virus 6 (HHV-6) can be found in Mayo Clin Proc 1999 Feb;74(2):163

Pathogenesis: 

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target cell for HHV-6 and HHV-7 is mature CD4+ T cell o HHV-6 can also infect fibroblast, epithelial and neural origin cell lines o CD46 is an essential membrane receptor for HHV-6 and is present on all nucleated cells o HHV-7 uses CD4 receptor as cellular receptor effects on immune system o enhancement of natural killer cell activity shown for HHV-6 and HHV-7 o enhancement of interleukin-15 shown for HHV-6 and HHV-7 o induction of other cytokines shown for HHV-6 o suppression of peripheral blood mononuclear cell proliferation shown for HHV-6 after primary infection, viral genome persists in peripheral blood mononuclear cells viral replication slow and lytic HHV-6 may persist in salivary glands and be transmitted via oral secretions from adults to infants human herpesvirus-6 (HHV-6) identified in saliva and stool from 20 infants with exanthem subitum, suggesting route of transmission; HHV-6 also detected in saliva of about half of 15 parents of patients and about half of 21 control parents (Pediatrics 1998 Oct;102(4):900) transmission in utero or by transplantation (blood, bone marrow, organs) may occur risk of transmission based on systematic literature review o moderate risk of transmission (10-30%) o incubation period 10-15 days, based on moderate evidence (well-designed study with 5-50 subjects) o duration of shedding not known, might be lifelong, based on limited evidence o period of infectiousness not known, might be lifelong, based on limited evidence o serial interval (interval between onset of clinical disease in index case and secondary case) 5-15 days (median 10 days), based on moderate evidence (well-designed study with 5-50 subjects) o no recommended exclusion period from school, based on moderate evidence (well-designed study with 5-50 subjects)  exclusion not required as this is generally a mild illness in childhood

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exclusion will not be fully effective because asymptomatic infections occur and may be involved in transmission  most cases occur before preschool or school age Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

Likely risk factors: 

female sex and having older siblings are risk factors for primary HHV-6 infection; prospective cohort of 277 children followed from birth through age 2 years, saliva tested weekly for HHV-6 DNA using polymerase chain reaction; primary HHV-6 infection occurred in 130 children (47%) but study limited by high dropout rates (median follow-up 60 weeks), cumulative incidence of primary HHV6 infection 40% at age 12 months and 77% at age 24 months among subjects completing follow-up, peak age of acquisition between 9 and 21 months; acquisition of HHV-6 associated with female sex (adjusted hazard ratio 1.7, 95% CI 1.2-2.4) and having older siblings (adjusted hazard ratio 2.1, 95 % CI 1.4-2.9) (N Engl J Med 2005 Feb 24;352(8):768)

Possible risk factors: 

risk factors for HHV-6 seropositivity in young children were low income and multiple siblings, and risk factors for HHV-7 seropositivity were month of test and black race, in cross-sectional study of 164 children 12-31 months old; breastfeeding may be associated with reduced risk for HHV-7 (Pediatr Infect Dis J 1998 Sep;17(9):792)

Complications and Associated Conditions Complications: 

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febrile seizures o febrile convulsions previously reported as associated with human herpesvirus 6, but not confirmed in subsequent studies (Pediatrics 1998 Feb;101(2):e3) o seizures occurred in 13% of 160 children presenting to emergency department with acute HHV-6 infection, but 12% of 401 matched controls with acute febrile illness, so no association with HHV-6 infection (N Engl J Med 1994 Aug 18;331(7):432) case reports of serious CNS complications have been published, including meningitis and fatal encephalitis; HHV-6 has been isolated from cerebrospinal fluid HHV-6 and HHV-7 identified in 17% of cases of infantile encephalitis in series of 156 United Kingdom children aged 2 months to 3 years admitted to hospital with encephalitis or fever and convulsions (Arch Dis Child 2005 Jun;90(6):619 in BMJ 2005 Jul 16;351(7509):133)

Associated conditions: 

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HHV-6 associated disease in immunocompromised hosts o may occur after transplantation  30-45% bone marrow transplantation recipients develop HHV-6 viremia within weeks  solid organ transplantation - up to 66% renal transplant patients have HHV-6 reactivation or reinfection  HHV-6 reactivation commonly follows treatment for organ rejection with OKT3 or antithymocyte globulin o HHV-6 reactivation may occur with HIV-1 infection o may cause bone marrow suppression, pneumonitis, encephalitis, graftversus-host disease, hepatitis, viral hemophagocytosis, idiopathic thrombocytopenic purpura HHV-6 may be associated with multiple sclerosis o human herpesvirus-6 has been associated with multiple sclerosis (Science 1997 Dec 5;278(5344):1710 in Pediatric Notes 1998 Jan 8;22(2):7, Nat Med 1997 Dec;3(12):1394 in Hosp Pract 1998 Apr;33(4);26), commentary can be found in Nat Med 1997 Dec;3(12):1321, commentary can be found in Nat Med 1998 May;4(5):537 o human herpesvirus 6 (HHV-6) identified in body fluids of 10 of 43 patients with multiple sclerosis and none of 34 healthy controls (J Infect Dis 2000 Nov;182(5):1321 in QuickScan Reviews in Fam Pract 2001 Mar;26(1):20)

History and Physical History: Chief concern (CC):     

fever rash mild diarrhea and cough are common convulsions, presumably febrile seizures, reported in up to 13% of children in one series, but not confirmed in other series comparing 80 children < 2 years old with primary HHV-6 infection during prospective monitoring vs. 80 matched controls without HHV-6 infection o 94% vs. 71% had any symptom (p = 0.004) o 58% vs. 14% had fever (p < 0.001) o 70% vs. 46% had fussiness (p = 0.009) o 66% vs. 46% had rhinorrhea (p = 0.02) o 26% vs. 11% had diarrhea (p = 0.05) o 24% vs. 3% had roseola (p = 0.003) o 39% vs. 19% had visit to physician (p = 0.009) o no child had seizures o no significant differences in rates of cough (34% vs. 33%) or vomiting (8% vs. 5%)

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Reference - N Engl J Med 2005 Feb 24;352(8):768

History of present illness (HPI):   

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child often appears healthy except for feeling hot abrupt high fever 103-106 degrees F (39.5-41.2 degrees C) for 1-5 days, most children have high fever lasting about 4 days rash most commonly occurs transiently at resolution of fever o erythematous macular or maculopapular rash in shawl area o rash lasts for 1-4 days o may appear on face and trunk, then peripherally may also present as fever without rash or rash without fever

Review of systems (ROS): 

loss of appetite, nausea and vomiting may occur

Physical: General physical: 

fever but otherwise well, normal exam

Skin: 

rash most commonly occurs transiently at resolution of fever o erythematous macular or maculopapular rash in shawl area o may appear on face and trunk, then peripherally

HEENT: 

findings are neither sensitive nor specific but may include o bulging anterior fontanelle o edematous eyelids o erythematous conjunctivae o pharyngitis, erythematous papules in pharynx o oral lesions - small macular spots on soft palate (Nagayama's spots), specks, streaks, papules (lymphoid hyperplasia)

Neck: 

cervical adenopathy can be seen

Diagnosis Making the diagnosis:

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correct clinical diagnosis made in < 20% of cases, more commonly diagnosed as otitis media or a "virus" distinguished clinically from other infections by presentation with high fever followed by rash after fever subsides

Rule out:    

rubella scarlet fever - high fever and rash occur simultaneously measles - rash develops as fever increases morbilliform rash in immunized children not due to measles or rubella; study of 195 children with morbilliform rash and fever in English population with high vaccination coverage, 93 (48%) had laboratory confirmation of infection; causes were parvovirus B19 (17%), group A streptococcus (15%), human herpesvirus type 6 (6%), enterovirus (5%), adenovirus (4%) and group C streptococcus (3%) (Arch Dis Child 2002 Sep;87(3):202 in BMJ 2002 Sep 7;325(7363):554)

Testing overview: 

none necessary in most cases, clinical diagnosis

Blood tests: 

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up to 80% seropositive for human herpesvirus (HHV-6) antibodies o IgM typically occurs by day 5-7 of illness, peaks at 2-3 weeks, clears within 2 months o IgG 2-3 weeks after illness is more reliable white blood count (WBC) may increase initially, then often decreased (with decreased neutrophils and lymphocytosis), with return to normal after rash subsides

Other diagnostic testing:  

virus culture requires 1-3 weeks, rarely done polymerase chain reaction (PCR) may demonstrate viral DNA in serum, plasma or cerebrospinal fluid

Treatment Treatment overview: 

no treatment necessary, roseola resolves without sequelae

Medications: 

virus resistant to acyclovir, but susceptible to ganciclovir and foscarnet in vitro

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no clinical trials have been conducted, and ganciclovir and foscarnet have significant toxicity

Prognosis  

self-limited, resolves without sequelae unknown if important in future (EBV and CMV are important in transplants)

Prevention and Screening Prevention: 

no recommended exclusion period from school (UK expert Grade B, Level IIIV) o exclusion not required as this is generally a mild illness in childhood o most cases occur before preschool or school age o exclusion will not be fully effective because asymptomatic infections occur and may be involved in transmission o see Causes and Risk Factors section for information on risk of transmission based on systematic literature review o Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

Screening: 

not applicable

Guidelines and Resources Guidelines: 

expert guideline on exclusion policies for control of communicable disease in schools and preschools can be found in Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

Review articles:   

review of generalized rash (differential diagnosis) can be found in Am Fam Physician 2010 Mar 15;81(6):726 review of generalized rash (diagnostic approach) can be found in Am Fam Physician 2010 Mar 15;81(6):735 review of fever with rash can be found in Am Fam Physician 2000 Aug 15;62(4):804, corrections can be found in Am Fam Physician 2001 Jul 15;64(2):220