01Approach to the Critical Patient/attcp42

Immediate stabilization

›Airway and seizure threats

›Seizure activity requiring immediate intervention

›Benzodiazepine for seizures lasting >5 minutes

›Midazolam 0.1–0.2 mg/kg IN or IV (max 5 mg)

›Diazepam 0.3 mg/kg IV or 0.5 mg/kg PR (max 10 mg)

›Airway protection during convulsion

›Lateral decubitus positioning

›Suction available at bedside

›Post-ictal airway reassessment

›If GCS does not return to baseline, escalate to resus bay

›Consider CT head if focal seizure or prolonged post-ictal state

›Hemodynamic assessment

›Circulatory compromise triggers

›SBP below age-appropriate norms

›Capillary refill >3 seconds

›Mottled skin or cool peripheries

›If hemodynamically unstable, IV access and isotonic fluid 10–20 ml/kg bolus

›Reassess after each bolus for response

›Exclude sepsis as concurrent process

Monitoring and targets

›Monitoring bundle

›Continuous cardiac and pulse oximetry monitoring

›SpO2 target >95%

›HR and RR trending for deterioration

›Repeat neurological assessment every 15–30 minutes in seizing or post-ictal child

›GCS or AVPU scale

›Pupillary symmetry and reactivity

02History/hx64

Presenting syndrome

›Fever characteristics

›Abrupt onset high fever (mean 39.4–39.7°C)

›Duration 3–5 days (mean 4.1 days)

›Often high and persistent without clear source during pre-eruptive phase

›Rash timing relative to fever

›Rash appears as fever resolves (hallmark temporal relationship)

›Rash duration 3–4 days

›Associated symptoms

›Irritability (often prominent during febrile phase)

›Disproportionate to degree of fever

›Reassurance for caregivers that this is characteristic

›Diarrhea (68% of confirmed cases)

›Mild and self-limited

›Assess hydration status

›Upper respiratory symptoms

›Cough in ~50%

›Rhinorrhea or nasal congestion in ~41%

›Decreased oral intake

›Risk of dehydration in the febrile phase

›Small frequent volumes preferred

Alarm features

›Seizure history

›Febrile seizures occur in 8–13% of primary HHV-6B infections

›HHV-6 accounts for one-third of all febrile seizures in children ≤2 years

›Simple vs complex or focal distinction critical

›Family history of febrile seizures increases recurrence risk

›Prior febrile seizures carry ~30% recurrence risk

03Physical Exam/exam64

Vital signs

›Temperature assessment

›High fever typically 39–40.5°C during pre-eruptive phase

›Tachycardia proportional to fever expected

›Fever resolution coincides with rash appearance

›Absence of fever with rash onset is reassuring

›Confirms transition from febrile to exanthematous phase

›Haemodynamic stability markers

›Heart rate age-appropriate range

›Tachycardia beyond fever-driven increase suggests illness severity

›Capillary refill time

›>3 seconds warrants fluid assessment

›Skin perfusion

›Mottling, pallor, or poor colour indicates concern

Skin exam

›Rash characteristics

›Blanching pink macules or maculopapules

›Trunk and face predominant distribution

›Non-pruritic and non-tender

›Rash timing and appearance

›Appears as fever breaks (pathognomonic sequence)

›Lasts 3–4 days then resolves without desquamation

›Negative features that help confirm roseola

›No vesicles (excludes varicella and herpes)

›No petechiae or purpura (excludes meningococcemia)

›No slapped cheek appearance (excludes fifth disease)

Head and neck

›Fontanelle assessment

›Bulging anterior fontanelle in ~26% of confirmed cases

›Benign in roseola but requires clinical judgment

›If bulging with meningismus or toxic appearance, LP indicated

›HEENT findings

›Periorbital and eyelid oedema in ~30%

›Bilateral and non-pitting; characteristic of roseola

›Nagayama spots (pharyngeal papules) in ~65%

›Erythematous papules at soft palate and uvula junction

›Pre-eruptive finding, helps clinch diagnosis in the febrile phase

›Erythematous or inflamed tympanic membranes

›Common finding leading to misdiagnosis as otitis media

›Landmark NEJM study: 30% given erroneous "fever with otitis" diagnosis

›Lymphadenopathy

›Cervical lymphadenopathy in ~31%

›Mild, mobile, non-tender

›Suboccipital and posterior cervical nodes common

Neurological exam

›Level of consciousness

›GCS or AVPU assessment

›Expected: Alert and irritable but consolable between fever spikes

›Concern if lethargic or unresponsive beyond post-ictal period

›Meningeal signs

›Neck stiffness and Kernig/Brudzinski signs

›Absence of meningismus expected in uncomplicated roseola

›Positive signs prompt LP to exclude meningitis

›Neurological deficits

›Focal motor weakness, abnormal eye movements

›Not expected in typical roseola

›Focal deficits require neuroimaging and specialist consultation

PITFALLS

›Diagnostic pitfalls during the pre-eruptive febrile phase

›Roseola cannot be diagnosed before the rash appears

›Pre-eruptive phase mimics bacterial sepsis, UTI, and occult bacteremia

›Landmark NEJM study: 29% received "fever of undetermined cause/possible sepsis" diagnosis

›Nagayama spots may not be looked for or recognized

›Pre-eruptive pharyngeal papules help guide diagnosis before rash

›Bulging fontanelle leading to unnecessary LP

›Benign in roseola but cannot be distinguished from meningitis without LP if toxic

›Empiric antibiotics given during febrile phase

›Many children receive antibiotics before roseola diagnosis is established

›Review need for antibiotics once rash confirms viral diagnosis

04Differential Diagnosis/ddx52

Cannot-miss diagnoses

›Bacterial meningitis and sepsis

›ICD-10 G00.9 / A41.9

›Toxic appearance, meningismus, petechiae/purpura

›Febrile infant <60 days always requires rigorous sepsis evaluation

›Differentiating features from roseola

›Ill appearance, non-blanching rash, photophobia distinguish meningitis

›Kawasaki disease

›ICD-10 M30.3

›Prolonged fever >5 days with conjunctival injection, mucositis, extremity changes, lymphadenopathy

›Cannot-miss diagnosis; coronary artery aneurysm risk

›Differentiating from roseola

›No conjunctivitis in roseola; fever in roseola typically <5 days

›Meningococcemia

›ICD-10 A39.2

›Non-blanching petechial or purpuric rash with fever

›Differentiating from roseola: roseola rash is blanching

Common viral mimics

›Measles (rubeola)

›ICD-10 B05.9

›Cough, coryza, conjunctivitis (3 Cs), Koplik spots

›Rash starts at hairline and spreads cephalocaudally while fever persists

›Differentiating from roseola

›No 3 Cs in roseola; rash in roseola appears after fever resolution

›Erythema infectiosum (fifth disease, parvovirus B19)

›ICD-10 B08.3

›Slapped cheek appearance, low-grade fever, lacy reticular limb rash

›Differentiating from roseola: no slapped cheek in roseola

05Laboratory Tests/lt47

Routine labs

›Complete blood count

›Characteristic pattern in primary HHV-6 infection

›Leukopenia (mean WBC 8,900/mm3)

›Lymphopenia

›Neutropenia

›Clinical utility

›Distinguishes HHV-6 from typical bacterial infection (bacterial: leukocytosis)

›Not required in well-appearing child with classic rash presentation

›Urinalysis

›Indication per AAP guidelines

›Febrile infants <24 months without clear fever source

›Obtain during the pre-eruptive febrile phase before diagnosis is established

›Interpretation

›Positive UA does not exclude concurrent HHV-6; both can coexist

›CRP and procalcitonin

›Risk stratification for bacterial superinfection

›CRP mildly elevated in HHV-6 but typically lower than bacterial infection

›Procalcitonin may be elevated in HHV-6 but lower than in bacteremia

›Use in combination with clinical picture, not as sole decision tool

Labs for severe or atypical presentations

›Blood culture

›Indications

›Ill-appearing or toxic febrile infant

›Febrile infant <60 days (per AAP sepsis evaluation pathway)

›Prior to antibiotics when clinically feasible

›Liver function tests

›Indication

06Diagnostic Tests/dt57

Scoring Systems

›Severity stratification framework

›Mild (typical): High fever 3–5 days followed by maculopapular rash on defervescence

›Well-appearing child

›Resolution within 7–10 days

›Moderate: Single simple febrile seizure

›Returns to baseline within 60 minutes

›No focal deficits

›Severe: Febrile status epilepticus, encephalopathy, or disseminated disease

›Requires inpatient management

›More common in immunocompromised hosts

›Febrile seizure classification

›Simple febrile seizure criteria

›Generalised tonic-clonic, duration <15 minutes

›Single seizure within 24-hour period

›Returns to full baseline

›Complex febrile seizure criteria

›Focal features, duration >15 minutes, or multiple within 24 hours

›Does not return to baseline promptly

›Warrants further evaluation including neuroimaging

MRI

›MRI brain indications

›HHV-6 encephalitis evaluation (gold standard modality)

›Mesial temporal lobe involvement characteristic of post-transplant HHV-6 encephalitis

›Limbic encephalitis pattern on fluid-attenuated inversion recovery sequences

›Complex febrile seizure workup when clinically indicated

›Focal deficits, prolonged post-ictal state, or recurrent focal seizures

›Encephalopathy with altered mental status beyond post-ictal period

07Disposition/dispo40

Discharge criteria

›Safe discharge criteria (majority of cases)

›Clinical criteria

›Well-appearing child with classic rash (fever then rash sequence)

›Tolerating oral fluids

›No seizures, or single simple febrile seizure with return to baseline

›Social criteria

›Reliable caregiver present

›Caregiver able to recognise return-to-ED signs

›Access to follow-up

Admission indications

›Definite admission criteria

›Neurological emergency

›Status epilepticus or complex febrile seizure not at baseline

›Encephalitis or encephalopathy (altered mental status, focal deficits)

›Meningitis requiring LP results and IV antibiotics pending culture

›Systemic instability

›Hemodynamic compromise not responding to initial resuscitation

›Inability to maintain hydration orally

›Toxic or ill appearance with concern for bacterial superinfection

›Immunocompromised host with suspected HHV-6 disease

›Antiviral therapy consideration and infectious disease input

›Age-based protocols

›Febrile infant <60 days

›Full sepsis evaluation per AAP 2021 guidelines

›Admission typically required pending blood and urine cultures

Specialist consultation triggers

›Pediatric neurology

08Treatment/t55

Supportive care (mainstay)

›Antipyretic therapy for comfort

›Acetaminophen (paracetamol)

›Dose: 15 mg/kg every 4 hours (max 5 doses per 24 hours)

›Maximum single dose: 1 g

›Goal is comfort, not achievement of normothermia

›Ibuprofen (infants ≥6 months)

›Dose: 10 mg/kg every 6–8 hours

›Maximum single dose: 400 mg

›Avoid in infants <6 months

›Avoid aspirin in children

›Risk of Reye syndrome; contraindicated

›Hydration management

›Oral rehydration for mild to moderate dehydration

›Small frequent volumes of ORS (10 ml/kg/hour)

›Breast milk or formula to continue as tolerated

›IV fluid therapy if oral intake failed or moderate-severe dehydration

›0.9% NaCl or Ringer's lactate 20 ml/kg bolus

›Reassess response and ongoing fluid needs

Seizure management

›Acute seizure treatment (active seizure)

›Benzodiazepine first-line for seizure >5 minutes

›Midazolam 0.1–0.2 mg/kg IN or buccal (max 5 mg)

›Diazepam 0.3 mg/kg IV (max 10 mg) or 0.5 mg/kg PR (max 10 mg)

›Lorazepam 0.05–0.1 mg/kg IV (max 4 mg) if IV access available

›Second-line if seizure persists after 2 benzodiazepine doses

›Levetiracetam 40–60 mg/kg IV (max 3 g) over 15 minutes

›Fosphenytoin 20 mg PE/kg IV at 1–3 mg PE/kg/min

09Special Populations/sp45

Pregnancy

›Maternal HHV-6 primary infection in pregnancy

›HHV-6 reactivation during pregnancy

›Seroprevalence in pregnant women >95%; primary infection in pregnancy is rare

›Reactivation during pregnancy has been associated with adverse fetal outcomes in small case series

›Fetal and neonatal considerations

›Congenital HHV-6 infection via chromosomally integrated HHV-6 (ciHHV-6) is well-described

›ciHHV-6 is inherited; present in every cell; associated with developmental and neurological concerns under investigation

›Antiviral considerations in pregnancy

›No approved antiviral regimen for HHV-6 in pregnancy

›Ganciclovir is teratogenic in animals; use only if maternal benefit outweighs risk

›Infectious disease and maternal-fetal medicine consultation required

Geriatric

›HHV-6 in older adults

›Primary roseola is extremely rare in adults; almost all adults are seropositive

›Over 95% of adults carry latent HHV-6 from childhood primary infection

›HHV-6 reactivation in elderly or immunocompromised adults

›Limbic encephalitis and drug-induced hypersensitivity syndrome (DIHS/DRESS) are recognized reactivation syndromes

›Drug reaction with eosinophilia and systemic symptoms (DRESS): fever, rash, organ involvement 2–8 weeks after drug exposure

›HHV-6 in elderly transplant recipients

›Post-transplant encephalitis risk parallels that in younger immunocompromised patients

›Ganciclovir or foscarnet as per adult dosing with renal function adjustment

Pediatrics

›Typical age and clinical course

›Peak incidence 6–15 months

›Accounts for ~10% of ED visits for acute febrile illness in children <2 years

›20% of such visits in 6–12 month age group

›Self-limited course

10Background/b63

Epidemiology

›Incidence and prevalence

›Seroprevalence: >95% of children are HHV-6B seropositive by age 2

›Peak incidence age 6–15 months (waning maternal antibody window)

›Over 95% of adults carry latent HHV-6 from prior childhood infection

›ED burden

›Roseola accounts for ~10% of all ED visits for febrile illness in children <2 years

›In 6–12 month olds: ~20% of febrile ED visits

›Seizure burden

›HHV-6 causes ~8–13% of primary febrile seizures

›HHV-6 accounts for one-third of all febrile seizures in children ≤2 years

›Causative agents

›HHV-6B: ~90% of roseola cases

›Betaherpesvirus subfamily; roseolovirus genus

›HHV-7: minority of cases; typically presents slightly later (18–36 months)

›Second episodes of roseola often due to HHV-7 after prior HHV-6B infection

›Chromosomally integrated HHV-6 (ciHHV-6)

›Occurs in ~1% of the general population

›Viral DNA integrated in every cell

›High viral loads on PCR without active infection; clinical correlation required

Pathophysiology

›Primary infection mechanism

›Transmission via saliva from asymptomatic shedders

›HHV-6 actively shed in saliva of healthy adults

›No strict seasonal predilection; occurs year-round

›Viral tropism

›HHV-6 primarily infects CD4+ T lymphocytes

›Also infects monocytes, macrophages, dendritic cells, and CNS astrocytes

›Latency established in bone marrow progenitor cells, monocytes, and brain

›Fever and rash mechanism

›Febrile phase (days 0–4): primary viraemia and immune activation

›High-level viral replication with cytokine release (IL-6, TNF-alpha)

›Leukopenia and lymphopenia due to T-lymphocyte infection and depletion

›Rash phase (day 4–7): immune-mediated response

›Rash appears as viral replication controlled and fever resolves

›Immune complex deposition and T-cell mediated dermal response

›CNS involvement mechanism

›HHV-6 neurotropism

›Infects astrocytes and neurons, particularly in limbic structures

›Febrile seizures: cytokine-mediated lowering of seizure threshold

›Encephalitis: direct viral invasion of CNS parenchyma

›Bulging fontanelle mechanism

›Inflammatory oedema and transient CSF pressure increase

›Occurs in ~26%; does not consistently reflect meningeal infection

›Reactivation biology

›HHV-6 reactivates with immunosuppression

›Post-transplant setting: most clinically significant reactivation syndrome

›Triggers include corticosteroids, anti-rejection therapy, graft manipulation

›Can cause encephalitis, pneumonitis, bone marrow suppression, hepatitis

Therapeutic Considerations

›Rationale for supportive-only management in immunocompetent children

›Self-limited illness with excellent prognosis

›No antiviral demonstrates benefit in immunocompetent host

›HHV-6 intrinsically resistant to acyclovir (lacks thymidine kinase substrate)

›Ganciclovir mechanism and limitations

›Inhibits HHV-6 DNA polymerase; in vitro activity confirmed

›Clinical evidence limited to small transplant cohort studies

›Bone marrow toxicity limits use in non-life-threatening illness

›Antipyretic evidence base

›Antipyretics reduce discomfort but do not prevent febrile seizures

›AAP 2011 guidance: treat fever for comfort, not normothermia

›No study demonstrates febrile seizure prevention with scheduled antipyretics

›Febrile seizure prophylaxis evidence

›No role for antiepileptic prophylaxis after simple febrile seizure

›Risk-benefit ratio unfavourable; recurrence risk (~30%) does not justify prophylaxis

›Complex or status epilepticus: neurological consultation for individualised plan

11Patient Discharge Instructions/pdi34

copy discharge instructions

›What your child has

›Your child has roseola, a common and harmless viral infection caused by human herpesvirus 6

›It causes several days of high fever followed by a pink rash when the fever breaks

›The rash is a sign that your child is getting better, not getting worse

›Roseola is self-limited and resolves completely in 7–10 days without complications in healthy children

›No specific treatment is needed beyond fever and comfort management

›Home care instructions

›Fever management

›Give acetaminophen (paracetamol) 15 mg/kg every 4–6 hours for comfort if needed

›Give ibuprofen 10 mg/kg every 6–8 hours for children 6 months and older

›Do not give aspirin to children (risk of Reye syndrome)

›Hydration

›Encourage frequent small amounts of clear fluids, breastmilk, or formula

›If diarrhea present, use an oral rehydration solution (Pedialyte or equivalent)

›Activity

›No restrictions once fever has resolved; the rash alone is not contagious

›Child was most contagious during the febrile phase before the rash appeared

›Return to emergency department immediately if

›Seizure of any kind, or seizure lasting longer than 5 minutes

›Call 911 if seizure does not stop within 5 minutes

›Lethargy, difficulty to wake, or unresponsiveness

›Bulging fontanelle combined with extreme irritability or stiff neck

›High fever persisting beyond 5–6 days or returning after defervescence

›Non-blanching rash (purple or red spots that do not turn white when pressed)

›Unable to keep fluids down or signs of dehydration

›No tears when crying

›No wet diapers for more than 8 hours

12References/r25

Guidelines and key sources

›Hall CB et al. Human herpesvirus-6 infection in children: a prospective study of complications and reactivation. New England Journal of Medicine. 1994

›Landmark NEJM prospective study establishing clinical features and ED diagnosis patterns

›Most common ED diagnoses were "fever with otitis" (30%) and "fever of undetermined cause" (29%)

›Stone RC, Micali GA, Schwartz RA. Roseola infantum and its causal human herpesviruses. International Journal of Dermatology. 2014

›Comprehensive clinical review including epidemiology, fever duration, and rash characteristics

›Asano Y et al. Clinical features of infants with primary human herpesvirus 6 infection. Pediatrics. 1994

›Clinical feature prevalence data including febrile seizure rates and exam findings

›Suga S et al. Clinical and virological analyses of 21 infants with exanthem subitum and CNS complications. Annals of Neurology. 1993

›CNS complication characterisation including bulging fontanelle (26%) and encephalitis

›Tembo J et al. Children infected by HHV-6B with febrile seizures are more likely to develop febrile status epilepticus. Journal of Medical Virology. 2018

›HHV-6B and febrile status epilepticus risk compared to other fever causes

›Tesini BL, Epstein LG, Caserta MT. Clinical impact of primary infection with roseoloviruses. Current Opinion in Virology. 2014

›Antiviral therapy review including ganciclovir and foscarnet evidence

›Sullivan JE, Farrar HC. Fever and antipyretic use in children. Pediatrics. 2011

›AAP policy statement: antipyretics for comfort, not normothermia; no seizure prevention

›Pantell RH et al. Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics. 2021

›AAP 2021 febrile infant guideline applicable to roseola pre-eruptive phase in young infants

›Smith DK, Sadler KP, Benedum M. Febrile seizures: risks, evaluation, and prognosis. American Family Physician. 2019

›Simple febrile seizure management: no prophylaxis; recurrence risk ~30%

›Cristoforo T et al. The not-so-soft spot: pathophysiology of the bulging fontanelle in association with roseola. Pediatric Emergency Care. 2020

›Bulging fontanelle in roseola: benign mechanism versus meningitis differentiation

›Agut H, Bonnafous P, Gautheret-Dejean A. Human herpesviruses 6A, 6B, and 7. Microbiology Spectrum. 2016

›Comprehensive virology review including reactivation biology and antiviral susceptibility

›Pellett PE et al. Chromosomally integrated human herpesvirus 6: questions and answers. Reviews in Medical Virology. 2012

›ciHHV-6 review: prevalence ~1%, clinical implications, PCR interpretation

Evidence & Review

Evidence & Review