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Fever Without Localizing Signs, 0-60 Days February 2021 TEXAS CHILDREN’S HOSPITAL EVIDENCE-BASED OUTCOMES CENTER Fever Without Localizing Signs (0-60 Days Old) Evidence-Based Guideline Definition: An acute febrile illness (temperature ≥100.4F Table 1. Signs and Symptoms of Shock (8,9) [38C]) with uncertain etiology after completion of a thorough Cold Warm Shock Non-specific history and physical examination. (1-3) Shock Etiology: The most common cause of fever without localizing Pulses Decreased Bounding signs (FWLS) is a viral infection. The challenge lies in the (central vs. or weak difficulty of distinguishing serious bacterial illness (SBI) from peripheral) viral illness in neonates and early infancy. (4,5) Capillary refill ≥3 sec Flash (<1 Inclusion Criteria: (central vs. sec) Age 0-60 days (Term infants ≥37 weeks gestation) peripheral) Neonates and infants without underlying conditions Mottled, Flushed, Petechiae Actual rectal temp ≥100.4F (38C) OR reported temp cool ruddy, below the (axillary or rectal) of ≥100.4F (38C) in home setting Skin erythroderma nipple, any (other than purpura Exclusion Criteria: face) History of prematurity Decreased, Underlying conditions that affect immunity or may otherwise irritability, increase risk of SBI confusion Toxic/Septic appearance inappropriate Receiving antibiotic treatment for FWLS crying or Routine vaccinations given within the previous 48 hours Mental drowsiness, Presenting with seizures status poor Requiring intensive care management interaction Identified focus of infection (e.g., cellulitis, acute otitis with parents, media in infants >28 days old) lethargy, diminished Differential Diagnosis: arousability, Meningitis obtunded Bone and joint infections *↑ HR followed by HR with BP changes will be noted as shock becomes Pneumonia uncompensated. Urinary tract infection (8,9) Sepsis/Bacteremia Table 2. Vital Sign Changes of Sepsis Heart Respiratory Enteritis Age Systolic BP Herpes Simplex Virus (HSV) infection Rate Rate Enterovirus 0d - 1m >205 >60 <60 Parechovirus >1m to 3m >205 >60 <70 SARS-CoV-2 Virus †BP changes are late signs of worsening condition. May also present with chills. (6,7) Toxic Criteria Infants that meet ANY of the toxic criteria should receive a full Diagnostic Evaluation: In this age group, bacterial pathogens sepsis workup and be admitted to the inpatient area for associated with FWLS may include Gram-positive organisms antibiotic therapy and observation (See Tables 1 & 2). (such as group B Streptococcus, Enterococcus, group A Streptococcus, Staphylococcus aureus, Listeria Signs/Symptoms include: monocytogenes) and Gram-negative organisms (such as Poor perfusion Escherichia coli, Enterobacter, Klebsiella). Streptococcus Capillary refill time >2 seconds pneumoniae is more likely to occur in infants >30 days old. Cyanosis (10,11) Lethargy Viral pathogens, such as enterovirus, adenovirus, herpes Unable to console simplex virus, influenza virus, and parainfluenza virus, are also Tachypnea or bradypnea a concern in this patient population. (12,13) There is limited Hypothermia (96.8F/36C) research available on the incidence of SARS-CoV-2 in infants, however preliminary data shows that children, including infants, seem to range from asymptomatic to moderate disease (14) severity. February 2021 History: Assess for Herpes Simplex Virus Onset of fever Evidence shows that there is an increase of the risk of Immunization status (15) mortality for disseminated HSV with each day of delayed Irritability treatment.(25) National guidelines support the consideration of Poor feeding HSV infection as a causative agent for neonates with Decreased urine output fever.(26) Laboratory evaluation for neonatal HSV infections Exposure to infectious agents should be performed for those with clinical findings suggestive Other sick contacts/family members of HSV infection or a maternal history of HSV. (27-30) Maternal fever at time of delivery Maternal Group B streptococcal vaginal colonization HSV Risk Factors (29) Maternal HSV infection Maternal primary HSV infection Maternal fever Physical Examination: Vaginal delivery Rectal temperatures are preferred to axillary or other methods Prematurity of temperature measurements. Neonatal seizures A thorough clinical history and physical examination are Vesicular rash essential to determine risk of SBI or identify focus of infection. (16,17) CSF pleocytosis (monocytosis) Elevated hepatic enzymes Table 3. Laboratory Tests Signs/Symptoms of Systemic HSV (30) 0-28 days 29 to 60 days Skin, eye, and mouth lesions/disease Complete blood count (CBC) X X with differential and platelets Seizures, lethargy, and fever Disseminated form - neonate presents with multi-organ Blood culture (BC) (obtain prior to antibiotic X X failure administration) The laboratory tests below are recommended if HSV Procalcitonin Optional X suspected. (26) Enterovirus CSF PCR High risk Specimens of skin vesicles for HSV culture or PCR (during peak season of May – X patients in peak CSF sample for HSV PCR October) season Whole blood sample for HSV PCR Urinalysis (UA) with micro and Swab specimens from the mouth, nasopharynx, culture (obtain specimen via X X conjunctivae, and anus for HSV culture (completed in- cath or SPA† only) hospital) or PCR (currently a send-out lab) Lumbar puncture* (LP) o To collect swab specimens for culture, the [gram stain, culture, cell count Based on risk practitioner may utilize one swab for the eye, X and diff, glucose, protein, viral classification mouth, nose and rectum in stated order. Different culture‡] swabs may be used for each specimen location; HSV testing (blood, CSF, however, if this method is used the practitioner If HSV risk factors present or swab specimens, cultures of should put all swabs in the same transport tube. worsening condition vesicles) Consider: (18-24) Stool for culture and presence of WBCs (if diarrhea present) Viral diagnostic testing or rapid tests (if respiratory symptoms) Chest X-ray (if respiratory symptoms; WBC >20,000/mm3 or ANC >10,000/mm3) Blood and/or CSF parechovirus PCR during peak season - May to October (if febrile and other viral/bacterial cultures negative) † Cath (transurethral catheterization) or SPA (suprapubic aspiration) *LP should be performed prior to antibiotic administration ‡ Tube #1 Glucose, protein Tube #2 Cell count & diff, Gram stain & culture HOLD Tube #3 in virology lab © Evidence-Based Outcomes Center 2 Texas Children’s Hospital February 2021 Critical Points of Evidence Evidence Supports Complete HSV testing and administer empiric acyclovir for neonates with no identified bacterial pathogen in CSF and the presence of CSF pleocytosis and/or exam, concern or possible maternal history of HSV, and/or toxic appearance. (25,27,31-34) – Strong recommendation, low quality evidence Remarks: Neonates with age less than or equal to 21 days present a heightened concern for HSV. Administer empiric antibiotic therapy of ampicillin and gentamicin for all neonates (0-28 days). If there is a concern for meningitis or CSF pleocytosis, cefTAZidime should be administered in lieu of gentamicin. (35,36) – Strong recommendation, low quality evidence In well-appearing infants 0 - 60 days of age with fever without localizing signs (FWLS) as well as negative cultures and laboratory assessments, discharge should be considered at 36 hours if not already done.(37-42) – Strong recommendation, low quality evidence Enterovirus testing (during peak season) should be utilized in addition to usual care in order to decrease length of stay. (43,44) – Strong recommendation, low quality evidence Infants 0-60 days with fever without localizing signs should be tested for enterovirus during peak season regardless of the presence of CSF pleocytosis (*TCH PCR positivity data plus expert consensus indicates that peak season will likely occur from May through October). (44-48) – Strong recommendation, low quality evidence Enterovirus CSF PCR should be used for testing when CSF specimen is available. (*This recommendation is also based on rapid turnaround time of CSF PCR as compared to serum PCR at TCH.) (18,48-50) – Strong recommendation, low quality evidence Enterovirus-positive infants 0-28 days old should have a minimum of 24 hours of hospital monitoring of bacterial cultures (18,19,48) – Weak recommendation, low quality evidence Enterovirus-positive infants 29-60 days old do not need further inpatient monitoring of bacterial cultures once enterovirus result is known. If otherwise meeting discharge criteria, enterovirus positive 29-60 day old infants can be discharged with a dose of ceftriaxone and close pediatrician follow-up. (*Recommendations based on expert consensus plus epidemiologic evidence showing low rates of SBI. SBI seems more common in neonates and those that are high risk.) (18,19,48) – Weak recommendation, low quality evidence Consider CSF parechovirus testing during peak season (May to October) when other viral (e.g., enterovirus, HSV) and bacterial etiologies have been ruled out. (20-23,51,52) – Weak recommendation, low quality evidence The diagnostic work-up for neonatal HSV infection should include all of the laboratory tests listed below. (26) o Specimens of skin vesicles for HSV culture or PCR o CSF sample for HSV PCR o Whole blood sample for HSV PCR o Swab specimen from the mouth, nasopharynx, conjunctivae, and anus for HSV culture (completed in-house) or PCR (currently a send-out lab) . Remarks: To collect swab specimens for culture, the practitioner may utilize one swab for the eye, mouth, nose and
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