Roseola

What is Roseola (Exanthem subitum)

Roseola is a common viral infection that causes a high fever and a rash.

It occurs most often in children who are between the ages of 6 months and 3 years old.

Roseola is also called roseola infantum, sixth disease, and exanthem subitum.

Interesting Facts of Exanthem subitum

1. Exanthem subitum (ie, roseola, sixth disease, 3-day fever) is a common acute childhood illness caused by a viral pathogen—usually human herpesvirus 6 (HHV-6B)—characterized by high fever lasting for several days followed by development of rash when fever abates
2. Typical age range is 6 months to 3 years 
3. High fevers are characteristic; pale pink macular rash usually begins on the neck and trunk, then spreads to proximal extremities; rash usually spares distal extremities and face; eruption may be evanescent, lasting 2 to 48 hours 
4. Diagnosis is primarily clinical, based on presenting manifestations with exclusion of alternative diagnoses 
5. Differential diagnosis for fever and rash in children is extensive; some important diagnoses in the differential may include rubeola, rubella, drug eruption, Kawasaki disease, fifth disease, Rocky Mountain spotted fever, infectious mononucleosis, and scarlet fever
6. Many conditions in the differential may be distinguished clinically by patient age, immunization status, presence of ill exposures, recent travel, use of medications, general appearance, and rash characteristics (appearance, distribution, temporal relationship to fever, and evolution over time)
7. Self-limiting in immunocompetent patients and requires supportive care only; complete recovery with no significant sequelae is typical 
8. The vast majority of children with exanthem subitum should not be treated with anti-viral medications; these are reserved for the care of immunocompromised patients
9. Febrile seizures are a common complication and develop in up to 15% children with primary HHV-6B infection

Exanthem subitum (ie, roseola, sixth disease, 3-day fever) is a common acute childhood illness caused by a viral pathogen—usually human herpesvirus 6B (HHV-6B)—characterized by high fever lasting for several days followed by development of rash when fever abates 

Typical age range of affected patients is 6 months to 3 years 

What are the causes of Roseola?

Roseola is usually caused by a virus called human herpesvirus 6. Occasionally, it is caused by human herpesvirus 7. These viruses are not the same as the virus that causes oral or genital herpes simplex infections.

Children can get the virus from other infected children or from adults who carry the virus through saliva or respiratory droplets.

Causes

• Primary infection with human herpesvirus 6 variant B (HHV-6B) is the cause of most cases 
  • Congenital infection occurs in about 1% of newborns; no known clinical disease or congenital malformations are associated with congenital infection 
  • Incubation averages about 9 to 10 days 
  • Primary route of transmission is thought to be saliva; virus replicates in salivary glands and remains latent in lymphocytes and monocytes after primary infection 
    • Reactivation is possible later in life, particularly with development of immunocompromised state
  • Duration of infectivity after primary infection can persist for weeks 
• Less commonly caused by HHV-7; enterovirus, adenovirus, and parainfluenza virus may cause similar febrile exanthems in infants and young children
• Chromosomal integration causes most congenital infections

What are the risk factors of Roseola?

Age

• Typical age range is 6 months to 3 years; peak age of primary infection with HHV-6B is 6 to 9 months 
• Uncommon in infants younger than 4 to 6 months owing to persistence of passive maternal antibody 
• Almost all children are infected with HHV-6B by age 2 years; ⁴ over 95% of adults are seropositive for HHV-6B 

What are the signs or symptoms?

Roseola causes a high fever and then a pale, pink rash. The fever appears first, and it lasts 3–5 days. During the fever phase, your child may have:

• Fussiness.
• Poor appetite.
• Stuffy (congested) or runny nose.
• Swollen eyelids.
• Swollen glands in the neck, especially the glands that are near the back of the head.
• A poor appetite.
• Some loose stools or diarrhea.
• A cough.
• Fits of uncontrolled movements (seizures). Seizures that come with a fever are called febrile seizures.

The rash usually appears 12–24 hours after the fever goes away, and it lasts 1–3 days. It usually starts on the chest, back, or abdomen, and then it spreads to other parts of the body. The rash can be raised or flat. As soon as the rash appears, most children feel fine and have no other symptoms of illness.

Clinical Presentation

History

• Classic presentation (high fever followed by rash upon defervescence) develops in about 20% to 25% of affected infants and young children in United States; primary HHV-6B infection in Japan results in fever and rash in up to 75% of patients 
• Many infants and children present with febrile seizure
• Prodrome
  • Sudden onset of high fever (39 °C to 41 °C) typically lasting 1 to 5 days 
    • About 15% of children remain febrile for 6 or more days 
  • Other possible associated manifestations include rhinorrhea, headache, vomiting, and diarrhea
  • Activity remains essentially normal
• Exanthem
  • Classically develops after defervescence; may be concurrent with fever
  • Morbilliform rash usually starts on trunk and neck, then spreads outward to involve proximal extremities
  • Rash usually spares distal extremities and is less prominent on the face
  • Eruption typically lasts about 1 to 3 days but may be as short as several hours and evanescent in nature 
  • Rash is nonpruritic and not painful
• No seasonal predilection exists; infection may occur throughout the year
• Most infections are sporadic without known ill contact; occasional outbreaks develop, particularly in day care settings
• Many infections with HHV-6B present with nonspecific fever, with or without an appreciable rash 
• Mononucleosislike syndrome is an uncommon presentation, occurring in about 5% of patients 

Physical examination

• Generally, children are active, alert, and well-appearing; however, they may be fussy in the presence of high fever
• Fever (high- or low-grade) may be sole manifestation of infection 
• Seizure may accompany fever (febrile seizure)
• Exanthem is variable in appearance; typical findings include:
  • Discrete, blanching, pale-pink macules 1 to 5 mm in diameter surrounded by a light halo 
  • Petechiae are lacking
  • Rash may become confluent
  • Palms and soles are spared
• Enanthem (Nagayama spots)
  • May develop as erythematous macules or papules on soft palate and uvula
  • Finding more common among Asian patients
• Cervical and postoccipital lymphadenopathy are characteristic 
• Tympanic membrane erythema, often bilateral, suggests myringitis and may be present 
• Fullness to anterior fontanelle is commonly reported without other meningeal signs (eg, no irritability, no meningismus); fontanelle should not be tense 
• Mild periorbital edema with eyelid swelling and mild palpebral conjunctival injection may be identified in some patients

How is this diagnosed?

The diagnosis of roseola is based on your child’s medical history and a physical exam.

Your child’s health care provider may suspect roseola during the fever stage of the illness, but he or she will not know for sure if roseola is causing your child’s symptoms until a rash appears.

Sometimes, your child may have blood and urine tests during the fever phase to rule out other causes.

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis is primarily clinical, based on presenting manifestations with exclusion of alternative diagnoses 
  • Strongly consider as cause for otherwise unexplained high fever in a relatively well-appearing young child
  • Establish clinical confirmation with appearance of rash after fever abatement
• Confirmatory testing methods are available; however, laboratory diagnosis does not usually influence clinical management 
  • Can aid in decision to initiate antiviral treatment or limit empiric antibiotic treatment in select immunocompromised patients or patients with severe, atypical presentations 
  • A combination of serologic testing and polymerase chain reaction for HHV-6B may be used to confirm diagnosis when indicated; culture is gold standard but available only in research laboratories 
  • Primary infection may be confirmed by either: 
    • Demonstration of active viral replication (eg, detection of viral DNA by polymerase chain reaction) in conjunction with negative serology (followed by seroconversion) 
    • 4-fold rise in antibody titer in an infant with maternal antibodies (infants aged about 6 months or younger) 
• Other standard tests may be obtained during febrile period—before rash appearance—to evaluate high fever of undetermined origin and exclude serious bacterial infection
  • CBC with differential, blood culture, urinalysis with microscopy, and urine culture may be obtained

Laboratory

• Serology
  • A variety of commercially available platforms may be used to measure antibodies to HHV-6B in serum or plasma, including indirect immunofluorescent antibody assay, neutralization assay, immunoblot, and ELISA 
    • Conduct testing only if confirmation is needed (eg, treatment is under consideration for severe or unusual manifestations, typically in immunocompromised patients) and if done, draw anti–HHV-6B IgG at baseline, as well as 4 weeks later 
  • Anti–HHV-6B IgG
    • Present from 2 to 4 weeks after illness onset and persists indefinitely 
    • Seroconversion between acute and convalescent samples provides strong evidence for recent primary infection 
      • However, 4-fold rise in antibody titer alone is not absolute and conclusive evidence for new infection; increase may occur with reactivation and in association with other infections, particularly other β-herpesvirus infections 
    • Absence of IgG in an infant older than 6 months combined with presence of replicating virus is strong evidence of primary infection 
  • Anti–HHV-6B IgM
    • Assays have proved unreliable (not especially helpful) for detecting primary or reactivated infection 
• Viral culture
  • Gold standard method to document active viral replication 
  • HHV-6B may be cultured from saliva; however, not often used as culture results are delayed and methodology is only available at select research laboratories 
• Polymerase chain reaction
  • Methods to identify active viral replication 
    • Polymerase chain reaction performed on acellular fluids (eg, plasma)
    • Reverse transcription polymerase chain reaction performed on peripheral blood mononuclear cells
  • Detection of HHV-6B DNA may not differentiate between new infection, persistent infection, or chromosomal integration (ciHHV-6B); interpretation of results may be confounded by: 
    • Asymptomatic reactivation of latent HHV-6B in patients who have previously seroconverted
    • Presence of chromosomally integrated HHV-6B (ciHHV-6B)
  • Note that detection of HHV-6B DNA in children younger than 2 years is not considered specific enough to exclude serious bacterial infection 
  • Interpret detection of HHV-6B DNA in cerebrospinal fluid with caution as presence only rarely correlates with clinical disease outside of severely immunocompromised states
• CBC and bacterial blood culture
  • Leukocytosis is common during first day of illness 
  • Leukopenia, relative neutropenia, relative lymphocytosis, and mild atypical lymphocytosis develop after first day and are self-limiting 
  • Mild thrombocytopenia may develop 
• Urinalysis with microscopy and culture
  • Sterile pyuria is not uncommon; may occur in up to about 13% of children with exanthem subitum

Differential Diagnosis

Most common

• Many conditions in the differential may be distinguished clinically by patient age, immunization status, presence of ill exposures, recent travel, use of medications, general appearance, and rash characteristics (appearance, distribution, temporal relationship to fever, and evolution over time)
• Rubeola
  • Highly contagious, acute viral respiratory illness caused by rubeola virus; most common in infants and unimmunized patients; presents similarly to exanthem subitum with high fever and rash
  • Areas of endemicity are found in many countries in Europe, the Middle East, Asia, the Americas, and Africa 
  • Differentiating clinical features may include:
    • General ill appearance in patients with rubeola and overall well appearance in patients with exanthem subitum
    • Presence of ill contact, international travel to area of rubeola endemicity, and nonimmunized status suggest rubeola
    • Rubeola prodrome often includes symptoms such as cough, conjunctivitis, and coryza, which are either absent or not prominent in exanthem subitum
    • Koplik spots (small white lesions with blue-gray center on erythematous base) adjacent to molars are pathognomonic for rubeola; may appear 1 to 4 days before rash 
    • Rash
      • Location: In rubeola, characteristically begins a few days after prodrome and onset of fever, begins on face and neck then progresses in cranial-to-caudal manner; in exanthem subitum, rash starts centrally on trunk and progresses outward to involve proximal extremities and spares the face
      • Appearance: rubeola rash often begins as maculopapular eruption, then may evolve more of a confluent eruption, particularly on face and neck; petechiae and hemorrhage may develop in severe cases. In exanthem subitum, petechiae and hemorrhagic appearance do not develop
      • Duration: rubeola rash persists for about 5 days and tends to clear in a cranial to caudal fashion; fever persists until several days after appearance of rash. In exanthem subitum, fever usually abates as rash appears 
  • Confirm diagnosis of rubeola with serology for antibody titers (significant rise in measles virus IgG or presence of measles virus IgM) or polymerase chain reaction for viral RNA in naso- or oropharyngeal secretions or urine 
• Rubella
  • Acute, moderately contagious viral infection caused by rubella virus; most common in unvaccinated patients (eg, immigrants); presents similarly to exanthem subitum with fever and rash
  • Illness is usually mild in immunocompetent patients 
  • Areas of endemicity include Africa, the Middle East, and South and Southeast Asia; incubation ranges from 12 to 24 days; disease has been eradicated secondary to vaccination programs in the Americas; peak incidence is late winter and early spring 
  • Differentiating clinical features may include:
    • Presence of ill contact, international travel to area of rubella endemicity, and nonimmunized status suggest rubella 
    • Presence of prominent and tender posterior cervical, posterior auricular, and suboccipital lymphadenopathy suggests rubella more so than exanthem subitum; lymphadenopathy typically occurs for up to a week before rash and persists while rash is present 
    • Fever associated with rubella is usually low-grade as opposed to typically high fever associated with exanthem subitum. Fever, when present, may occur simultaneously with rash in rubella; in patients with exanthem subitum, rash typically develops after defervescence 
    • Maculopapular rash begins on face and scalp, then spreads to trunk and extremities, lasts 3 to 5 days, and typically does not become confluent; exanthem subitum rash usually starts on the trunk and spreads peripherally 
    • Forchheimer spots (red macules on soft palate) are more common in patients with rubella and may become petechial; in contrast, enanthem associated with exanthem subitum is uncommon in patients residing in the United States and does not typically become petechial 
  • Confirm diagnosis of rubella with serology (presence of rubella IgM or 4-fold or greater rise from acute to convalescent rubella IgG titers) or rubella RNA detection by reverse transcription polymerase chain reaction 
• Fifth disease (erythema infectiosum) (Related: Parvovirus B19 Infection and Fifth Disease)
  • Illness caused by B19 virus (human parvovirus B19); school aged children are most common age group affected; presents similarly to exanthem subitum with rash and sometimes fever 
  • Most commonly presents in winter and spring; distribution is worldwide; epidemics often develop every 3 to 4 years
  • Differentiating clinical features may include:
    • Age (older age range for fifth disease than typical for exanthem subitum) and presence of ongoing fifth disease epidemic in the community (exanthem subitum does not typically occur in epidemics)
    • Mild illness with low-grade or absent of fever is typical for fifth disease; in contrast, high fever is typically present in exanthem subitum
    • Rash associated with fifth disease differs from that of exanthem subitum 
      • Classic fifth disease rash begins with a slapped cheek appearance associated with circumoral pallor for 2 to 4 days
      • Facial rash is followed by lacy, reticular, evanescent maculopapular rash on the trunk and extremities; may worsen with exposure to sunlight, heat, exercise, extreme emotion, and stress; may wax and wane for 1 to 6 weeks
      • Facial rash is uncommon in exanthem subitum
  • Diagnosis is usually based on characteristic clinical presentation; when necessary, confirmation can be achieved with serology for human parvovirus B19 IgM or reverse transcription polymerase chain reaction for human parvovirus B19 DNA 
• Kawasaki disease
  • Acute vasculitis syndrome of unknown etiology that can lead to coronary artery aneurysms; over 80% of affected patients are younger than 5 years; may present similarly with high fever and rash; sterile pyuria is common 
  • Incidence is highest among children residing in East Asia, particularly Japan
  • Kawasaki disease may present with a number of manifestations, all of which may not be present at the same time
    • Bilateral conjunctival injection
    • Oral findings: strawberry tongue, red cracked lips, oropharyngeal erythema
    • Cervical lymphadenopathy (node enlargement greater than 1.5 cm diameter) 
    • Rash: polymorphous, often appears within 5 days of fever onset; most common appearance is diffuse and maculopapular, sparing face 
    • Extremity changes: puffy hands and feet, erythematous palms and soles, desquamation involving fingers and toes (late finding)
  • Features distinguishing Kawasaki disease from exanthem subitum may include general ill appearance and extreme fussiness, striking conjunctival injection, oropharyngeal and extremity changes, longer duration of fever, and development of thrombocytosis late in disease course
  • Kawasaki disease is a diagnosis usually established by clinical criteria (ie, fever for at least 5 days, exclusion of other illness accounting for manifestations, and 4 out of 5 additional clinical criteria) 
• Drug eruption
  • Cause is thought to be delayed (type IV) hypersensitivity reaction; develops 4 to 21 days after initiation of new medication or after 1 to 2 days in previously sensitized patient 
  • Common drug classes that result in drug eruption include antiepileptics and antibiotics
  • Presents similarly with symmetrical erythematous macules and papules that begin on trunk and evolves rapidly; low-grade fever may associated with eruption; most drug rashes resolve within 1 to 2 weeks of discontinuing offending agent 
  • Mucous membrane involvement is not typical, and when present, is indicative of an increasingly severe drug reaction (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS [drug eruption with eosinophilia and systemic clinical manifestations])
  • In contrast to exanthem subitum, drug eruption rash is typically pruritic and duration of rash is longer than the typical 2 to 48 hours of exanthem subitum
  • Differentiate by clinical presentation and course of eruption; allergy testing may be required to definitively confirm drug allergy when diagnosis remains in question 
• Febrile bacterial illness
  • Bacteremia and urinary tract infection may be a concern during febrile phase of illness when characteristic exanthem subitum rash is absent
  • A complicating factor is that a minority of children with exanthem subitum will have sterile pyuria
    • If serum WBC count is less than 10,000/mm³ and pyuria is absent, risk of true (bacterial) urinary tract infection is low 
    • Presumably, an absence of frank bacteriuria and nitrates in urine diminish likelihood of bacterial urinary tract infection
  • Findings on CBC typical in children with exanthem subitum include leukopenia, relative neutropenia, and thrombocytopenia
  • Differentiation of exanthem subitum from bacteremia and urinary tract infection may be difficult during period of time before rash appears; development of characteristic rash with resolution of fever confirms clinical diagnosis of exanthem subitum
  • Definitive diagnosis of bacteremia and urinary tract infection are based on blood and urine culture results
• Scarlet fever (scarlatina)
  • Illness caused by pyrogenic exotoxin-producing Streptococcus pyogenes (group A β-hemolytic streptococci); usually affects children older than 2 years and is most common in 5- to 15-year age group; patients may report contact with an infected person
  • Presents similarly with sudden onset of fever and rash developing about 2 days after onset of infection; rash starts on trunk and spreads outward sparing the face; palms and soles are not involved 
  • Distinguishing features
    • Streptococcal contact and older patient age suggest scarlet fever
    • Occurs with or preceded by pharyngitis or tonsillitis; examination findings may include pharyngeal erythema and possibly exudate, palatal petechiae, significant cervical lymphadenopathy, and strawberry tongue
    • Quality of rash is different with erythematous, fine macules resembling a sunburn and sandpaper-like papules; may result in late desquamation of superficial skin on face, fingers, toes, and skin folds
    • Presence of Pastia lines (linear accentuation of rash in flexor creases and skin folds) and circumoral pallor
  • Confirm diagnosis of scarlet fever in appropriate clinical context with positive rapid strep antigen test or positive throat culture 
• Infectious mononucleosis
  • Epstein-Barr virus (HHV-4) has global distribution with seropositivity noted in up to 95% of adults worldwide; symptomatic infection tends to present in adolescents and young adults 
  • Initial symptoms often include severe fatigue and myalgias lasting a week or more before development of pharyngitis, fever, cervical lymphadenopathy, and hepatosplenomegaly; exudative tonsillitis with palatal petechiae is classic
  • Maculopapular rash involving trunk and arms may develop, often in association with antibiotic administration; however, rash may occur in the absence of antibiotic exposure. Rash usually lasts 1 to 6 days 
  • Typical CBC findings include lymphocytosis with greater than 10% atypical lymphocytes; elevation in aminotransferase levels (without frank hepatitis) is common 
  • Diagnosis is usually clinical; serology (Epstein-Barr virus–specific or heterophile antibody detection), reverse transcription polymerase chain reaction, and Epstein-Barr viral load may confirm acute infection

Disease	Populations most commonly affected	Prodrome and associated manifestations	Characteristics of exanthem	Cause, diagnosis, and empiric treatment (when indicated)
Measles (rubeola)	Infants and unvaccinated patients	Prodrome: cough, coryza, conjunctivitis, high fever, and Koplik spots General ill appearance Cervical lymphadenopathy and striking leukopenia may be present	Descending morbilliform rash with confluent maculopapular lesions starts on head and neck, then spreads down to  trunk and extremities; palm and soles may be involved  Rash becomes petechial and even hemorrhagic in some	Rubeola virus (Morbillivirus, in the family Paramyxoviridae) Laboratory confirmation may be established by measles antigen or RNA detection in infected tissues (including throat swabs), serology, or viral culture
Rubella (German measles, 3-day measles)	Immigrants and unvaccinated patients	Prodrome: upper respiratory tract infection symptoms and mild fever; tender posterior auricular, posterior cervical, and suboccipital lymphadenopathy, Forchheimer sign, transient arthralgia (more common in adolescents and adults) Maternal infection can result in congenital rubella	Descending rose-pink maculopapular rash starts on face and spreads down to trunk and extremities	Rubella virus (rubivirus in the Togaviridae family) Diagnosis is usually clinical  Laboratory confirmation may be established by serology, reverse transcription polymerase chain reaction for viral RNA, or culture
Roseola (exanthem subitum)	Patients aged 6 months to 3 years	High fever for several days, otherwise well appearance; erythematous macules on soft palate may develop in some	Discrete pale pink macules develop with defervescence, starting centrally on trunk and spreading to proximal extremities, sparing face Rash lasts hours to a few days; may become confluent	Human herpesvirus 6 (HHV-6) is primary cause; some other viruses implicated include HHV-7, coxsackievirus, adenovirus, and parainfluenza Diagnosis is usually clinical
Kawasaki disease	Infants and children	Fever for 5 days plus presence of variable combination of several findings: conjunctival injection, cervical adenopathy, extremity signs (eg, edema of hands and feet), oral signs (eg, red, fissured lips and/or strawberry tongue), general ill appearance	Polymorphous rash appears within 5 days of fever onset Most common presentation is erythematous maculopapular rash sparing face	Cause is unknown Diagnosis of complete Kawasaki disease is based on established clinical criteria
Fifth disease (erythema infectiosum)	School-aged children	Mild symptoms in immunocompetent, otherwise healthy children such as low-grade fever for 1 to 4 days and possibly arthralgias Aplastic crisis in patients with hemoglobinopathy Maternal infection can result in spontaneous abortion and hydrops fetalis	Facial rash appears when fever abates with red cheeks (slapped cheek)  Circumoral pallor is common Soft pink maculopapular rash may appear on trunk and extremities with central clearing (ie, reticular, lacy) persisting for a week or more Worsens with exposure to sunlight or heat	Parvovirus B19 Diagnosis is clinical Laboratory confirmation may be established by serology (positive parvovirus B19 IgM) or reverse transcription polymerase chain reaction for parvovirus B19 DNA when indicated
Rocky Mountain spotted fever	Any age Most common in North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri	Sudden onset of high fever, headache, vomiting, abdominal pain, and myalgia Periorbital edema and edema of dorsum of hands  Altered mental status and multiorgan system damage may develop	Rash develops 2 to 4 days after onset of fever Pink macules develop on ankles and wrists and spread to trunk May involve palms and soles Petechiae mark severe disease and often develop around day 5 or 6 of illness	Bacterial infection caused by Rickettsia rickettsii transmitted by tick bite; peak transmission is May through August and incubation is 3 to 12 days Diagnosis is clinical Early initiation of empiric antibiotic treatment (doxycycline in all age groups) is imperative; serology is unreliable for acute diagnosis (may be negative for first 7-10 days after infection) and polymerase chain reaction is insensitive  Isolation of organism from blood or detection in biopsy specimen is confirmatory
Meningococcemia	Infants and unvaccinated young adults Residents in group setting, travel to area of endemicity, and certain comorbidities (eg, compliment deficiency, asplenia, HIV infection) increase risk of infection	Fever, meningismus, positive Kernig and Brudzinski signs, headache, vomiting, photophobia, and altered mental status Ill appearance	Primarily truncal and extremity rash may be maculopapular, petechial, or purpural; usually begins as diffuse, erythematous, and maculopapular, evolving into petechiae and purpura	Bacterial infection caused by Neisseria meningitidis  Variety of diagnostic modalities exist including culture, Gram stain, polymerase chain reaction, and latex agglutination antigen detection Empiric initiation of antibiotics (ceftriaxone) is imperative when diagnosis is suspected pending confirmatory testing
Infectious mononucleosis	Adolescents and young adults May affect children	Classic presentation: exudative pharyngitis and cervical lymphadenopathy with or without palatal petechiae, prolonged fever, extreme fatigue, splenomegaly, atypical lymphocytosis, and high aminotransferase levels	Diffuse polymorphous (usually maculopapular, maybe urticarial, rarely petechial) rash on trunk and arms characteristically develops with antibiotic exposure Rash may develop without antibiotic exposure	Epstein-Barr virus Diagnosis is usually clinical Serology, reverse transcription polymerase chain reaction, and Epstein-Barr viral load may confirm acute infection
Scarlet fever (scarlatina)	Children aged 5 to 15 years	Sudden onset of fever and pharyngitis  Strawberry tongue, palatal petechiae, and circumoral pallor may be present	Red rash begins on groin and armpits, spreads to trunk, then outward to extremities typically sparing face, palms, and soles Sandpaperlike quality is classic appearance; Pastia lines Late desquamation	Erythrogenic toxin produced by Streptococcus pyogenes  Diagnosis may be made on clinical grounds and confirmed by rapid streptococcal antigen test or throat culture
Drug eruption	Usually 4 to 21 days after initiation of new drug or 1 to 2 days after drug exposure in previously sensitized patient Increased risk with antiepileptics and antibiotics	May be associated with low-grade fever, pruritus, and mild eosinophilia Mucosal involvement may be present in severe reactions May improve with antihistamines	Rapidly evolving, usually symmetrical, red maculopapular rash; distribution is often diffuse, primarily involving trunk and proximal extremities Rash fades within 1 to 2 weeks of discontinuing offending agent	Delayed (type IV) hypersensitivity reaction Diagnosis is usually based on clinical presentation and course of eruption

Citation: Data from CDC: Rocky Mountain Spotted Fever: Information for Healthcare Providers. CDC website. Reviewed February 19, 2019. Accessed February 20, 2020. https://www.cdc.gov/rmsf/healthcare-providers/index.html; Muzumdar S et al: The rash with maculopapules and fever in children. Clin Dermatol. 37(2):119-28, 2019; CDC: Meningococcal Disease. CDC website. Reviewed January 21, 2020. Accessed February 20, 2020. https://www.cdc.gov/meningococcal/index.html; Cohen JI: Human herpesvirus types 6 and 7 (exanthem subitum). In: Bennett JE et al, eds: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier; 2020:1891-6.e2; Gershon AA: Measles virus (rubeola). In: Bennett JE et al, eds: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier; 2020:2110-6.e2; Gershon AA: Rubella virus (German measles). In: Bennett JE et al, eds: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier; 2020:2007-12.e2; Brown KE: Human parvoviruses, including parvovirus B19V and human bocaparvoviruses. In: Bennett JE et al, eds: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier; 2020:1968-75.e3; Arango CA et al: 8 viral exanthems of childhood. J Fam Pract. 66(10):598-606, 2017; Kadambari S et al: Acute viral exanthems. Medicine. 45(12):788-93, 2017; and Muzumdar S et al: The rash with maculopapules and fever in adults. Clin Dermatol. 37(2):109-18, 2019.

How is this treated?

Roseola goes away on its own without treatment. Your child’s health care provider may recommend that you give medicines to your child to control the fever or discomfort.

Treatment Goals

• Provide supportive care with antipyretics and prevent dehydration with oral administration of fluids

Admission criteria

Concern for serious bacterial infection in a young child may require admission for further diagnostic and management considerations

Uncomplicated exanthem subitum in otherwise well-appearing and hydrated infant or child does not usually require admission; certain complications associated with infection (eg, repeated or prolonged febrile seizures) may require admission for treatment, monitoring, and exclusion of alternative diagnoses

Criteria for ICU admission

• Certain complications or severe manifestations associated with exanthem subitum may require admission to ICU (eg, febrile status epilepticus, meningoencephalitis, myocarditis)

Recommendations for specialist referral

• Consult infectious disease specialist for diagnostic and treatment considerations in patients with immunocompromised state

Treatment Options

Exanthem subitum is self-limiting in immunocompetent patients and requires supportive care only

HHV-6B may require treatment in immunocompromised patients and patients with severe manifestations (eg, encephalitis) 

• Drugs commonly used in consultation with infectious disease specialist include ganciclovir, foscarnet, and cidofovir 

Drug therapy

• Ganciclovir
  • For immunocompromised patients with HHV-6B infection
    • Ganciclovir Solution for injection; Infants, Children, and Adolescents: 5 mg/kg/dose IV every 12 hours for 1 to 3 weeks, followed by a maintenance dose of 5 mg/kg/dose IV every 24 hours to 5 times weekly, has been effective based on limited data in children and adults; higher doses (18 to 24 mg/kg/day) have also been used, without side effects. Ganciclovir +/- foscarnet is suggested by IDSA due to lack of therapeutic options.
    • Ganciclovir Solution for injection; Adults: 5 mg/kg/dose IV every 12 hours for 1 to 3 weeks, followed by a maintenance dose of 5 mg/kg/dose IV every 24 hours to 5 times weekly, has been effective based on limited data in adults. Ganciclovir +/- foscarnet is suggested by IDSA due to lack of therapeutic options.
• Foscarnet
  • For patients with AIDS and HHV-6B infection
    • Foscarnet Sodium Solution for injection; Adults and Adolescents: 90 mg/kg IV q12h or 60 mg/kg IV q8h is recommended by the CDC.
      • Adequate hydration is recommended both before and during treatment to minimize renal toxicity
• Cidofovir
  • Cidofovir Solution for injection; Adults and Adolescents†: 5 mg/kg/dose IV once per week for 2 weeks; must be given in conjunction with hydration and probenecid. 
  • Contraindicated in patients with:
    • Creatinine clearance of 55 mL/minute or less
    • Serum creatinine level greater than 1.5 mg/dL
    • Proteinuria dipstick of 2+ or higher (urine protein level of 100 mg/dL or more)

Nondrug and supportive care

• Encourage fluids to maintain hydration 
• Antipyretics for fever management 
• Standard precautions are recommended for isolating hospitalized patients 

Special populations

• Immunocompromised patients
  • HHV-6B reactivation occurs in immunocompromised hosts such as allogeneic hematopoietic stem cell transplantation recipients, those with solid organ transplants, and patients with HIV 
    • A large proportion of hematopoietic stem cell and organ transplant recipients reactivate HHV-6B with viral DNA in the peripheral blood 
  • HHV-6B is frequently associated with fever, diarrhea, mucositis, and cutaneous rashes early after transplant
    • Also associated with delayed hematologic recovery in hematopoietic stem cell transplant recipients; such infection should be suspected in cases of delayed hematopoietic reconstitution 
  • Limbic encephalitis is a well-documented manifestation of HHV-6B in immunosuppressed patients 
    • Patients present 2 to 6 weeks after hematopoietic stem cell or cord blood transplant with headache, confusion, and nonfocal neurologic abnormalities (eg, seizures, psychosis, cranial nerve deficits)
  • Antiviral therapy has been used successfully in some immunocompromised patients 
    • Although controlled studies demonstrating efficacy are few, anecdotal reports have suggested that patients with HHV-6B encephalitis respond to a 7-day course of ganciclovir or foscarnet 
    • The Infectious Diseases Society of America recommends either ganciclovir or foscarnet, or a combination of both to treat immunocompromised patients with HHV-6B encephalitis

Follow these instructions at home:

Medicines

• Give over-the-counter and prescription medicines only as told by your child’s health care provider.
• Do not give your child aspirin because it has been linked to Reye syndrome. Give aspirin only if told to do so by a health care provider.

General instructions

• Do not put cream or lotion on the rash unless instructed to do so by your child’s health care provider.
• Monitor your child’s temperature. If your child is less than 3 years old, use a rectal thermometer as instructed by your child’s health care provider.
• Keep your child away from other children until your child’s fever has been gone for more than 24 hours.
• Have your child drink enough fluid to keep his or her urine clear or pale yellow.
• Let your child wash his or her hands with soap and water often. If soap and water are not available, let him or her use hand sanitizer. You should wash or sanitize your hands often as well.
• Keep all follow-up visits as told by your child’s health care provider. This is important.

Contact a health care provider if:

• Your child acts very uncomfortable or seems very ill.
• Your child’s fever lasts more than 4 days.
• Your child’s fever goes away and then returns.
• Your child will not eat.
• Your child is more tired than normal (lethargic).
• Your child’s rash does not begin to fade after 4–5 days, or it gets much worse.

Get help right away if:

• Your child has a seizure.
• Your child is difficult to wake from sleep.
• Your child will not drink.
• Your child’s rash becomes purple or bloody.
• Your child’s neck becomes stiff.
• Your child who is younger than 3 months old has a temperature of 100°F (38°C) or higher.

Complications

• Febrile seizures (common)
  • Develop in up to 15% children with primary HHV-6B infection 
  • Most common in children aged 6 to 18 months; highest risk age group is 12 to 15 months 
  • Up to one-third of febrile seizures in children younger than 2 years are attributable to HHV-6B 
  • Seizures associated with HHV-6B are more likely to be complex (eg, partial, prolonged, repeated seizures associated with postictal paralysis) than febrile seizures not associated with HHV-6B 
    • Development of complex febrile seizures, particularly prolonged febrile seizures and febrile status epilepticus, often leads to hospitalization 
• Health care utilization
  • Up to 25% of all emergency department visits for fever in children aged 6 to 12 months are attributable to HHV-6B 
  • Hospitalization results from concern that serious bacterial infection may occur in a significant number of children presenting younger than 6 months, with primary infection seen in emergent settings 
  • Infants and very young children may require laboratory testing when presenting with high fever and minimal or no focus of infection on examination; blood and urine assessments may be obtained; lumbar puncture for cerebrospinal fluid may be considered if fontanelle is full (exanthem subitum can present with full fontanelle)
  • Results of urinalysis and/or urine microscopy concerning for urinary tract infection may confound the scenario (exanthem subitum may cause sterile pyuria); if empiric antibiotics are started and patient develops rash, confusion ensues regarding potential drug allergy
  • Findings suggestive of myringitis may be present on examination in children with exanthem subitum, leading to unnecessary antibiotic use for presumed bacterial otitis media; if patient then develops rash, confusion ensues regarding potential drug allergy 
• Rare complications from primary HHV-6B infection in otherwise healthy patients 
  • Encephalopathy, encephalitis, and meningitis
    • Noted in Japan more frequently than in the United States or Europe 
  • Hepatitis
    • May be chronic or fulminant, leading to hepatic failure 
  • Myocarditis 
  • Hemophagocytic syndrome 
  • Thrombocytopenic purpura 
• Reactivation of HHV-6B virus
  • Reactivation is generally asymptomatic in immunocompetent patients; however, encephalitis secondary to reactivation of HHV-6B may occur, albeit rarely, in immunocompetent patients 
  • Reactivation is very common in immunocompromised patients; serious illness may develop 
    • Solid organ and hematopoietic stem cell transplant recipients are among the groups at highest risk 
    • Fever and rash early after transplant are the most common manifestations 
    • Other presentations including dermatitis, giant cell hepatitis, pneumonia, encephalitis or encephalopathy, bone marrow suppression, delayed engraftment, graft-versus-host disease, and graft rejection 
    • Posttransplantation acute limbic encephalitis
      • Distinct syndrome associated with HHV-6B reactivation characterized by anterograde amnesia, seizures, insomnia, confusion, and SIADH 
      • Cord blood transplant recipients are at highest risk 
      • MRI findings include changes in gray matter in the medial temporal lobe 
      • Associated morbidity and mortality is high 
  • Confirmation of reactivation is complicated and requires presence of compatible clinical syndrome, evidence of HHV-6B viral replication, and exclusion of alternative diagnosis; determine appropriate testing in consultation with infectious disease specialist 
  • Antiviral therapy may be required to diminish severity of clinical course; data are limited, however, agents effective against cytomegalovirus are typically used given the similarity between cytomegalovirus and HHV-6B
• Congenital infection
  • Occurs in about 1% to 2% of neonates and is usually secondary to chromosomal integration (germline passage of maternal or paternal chromosomally integrated HHV-6B [ciHHV-6B]); a minority of infections are transmitted through transplacental infection 
  • Congenital infection is asymptomatic; clinical implications of ciHHV-6B are yet to be defined 
  • Interpretation of molecular testing for HHV-6B may be confounded by presence of ciHHV-6B

Prognosis

• Exanthem subitum is self-limiting in immunocompetent patients; complete recovery with no significant sequelae is typical 
• Risk of recurrent febrile seizures (febrile seizures with a future febrile illness) does not appear to be higher than risk associated with febrile seizures secondary to other non–HHV-6B causes 
• HHV-6B may require treatment in immunocompromised patients; morbidity and mortality may be high among immunocompromised patients 

Prevention

• No method exists to interrupt transmission 
  • General exposure prevention measures are ineffective given HHV-6B ubiquity and nearly universal childhood serum positivity 
• Exclusion criteria from day care and school are not rigorously standardized for infants and children with exanthem subitum 
  • Patients with sporadic cases of exanthem subitum are not generally considered to be contagious 

Summary

• Roseola is a common viral infection that causes a high fever and a rash.
• The rash usually appears 12–24 hours after the fever goes away, and it lasts 1–3 days.
• As soon as the rash appears, most children feel fine and have no other symptoms of illness. Roseola goes away on its own without treatment.

Sources

Arango CA et al: 8 viral exanthems of childhood. J Fam Pract. 66(10):598-606, 2017 Cross Reference