Fever Without Focus Management Birth to 3 Months

Aka: Fever Without Focus Management Birth to 3 Months, Fever in the Newborn, Neonatal Fever

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II. Precautions

  1. Protocols assume a full term, febrile infant without chronic medical conditions and no obvious infection source
  2. Febrile if Temperature >100.4 F (38 C) or hypothermic <96.8 F (36 C)
  3. Unwell or toxic appearing infants should undergo complete Sepsis evaluation
  4. Consult pediatrics in Preterm Infants, or those with chronic medical conditions
  5. Infants may be afebrile at clinical encounter, but febrile at home
    1. Serious Bacterial Infection may be present for Infants under age 1 month, despite lack of fever at visit
    2. Brown (2004) CJEM 6(5): 343-8 [PubMed]

III. Indications

  1. Nontoxic appearing young infant under age 3 months
    1. See Toxic Findings Suggestive of Occult Bacteremia
    2. Unwell. or toxic appearing infants should be treated as Neonatal Sepsis
  2. Fever over 100.4 F (38 C)
  3. No known infectious source
  4. No chronic medical conditions
  5. No history of prematurity
    1. Premature Infants under 3 months undergo full Neonatal Sepsis evaluation

IV. Approach: Protocol for Well Appearing Febrile Infants under age 60 days (Revise II, 2021, with added guidance up to 90 days)

  1. Age 0 to 21 days old: Perform a full Neonatal Sepsis work-up
    1. See Neonatal Sepsis
    2. Labs
      1. See Labs and Imaging below
      2. CBC with differential, Urinalysis with microscopic exam, Blood Culture, Urine Culture, Lumbar Puncture
      3. Also obtain Procalcitonin (PCT), C-Reactive Protein (CRP), basic metabolic panel, total Serum Bilirubin
      4. Respiratory diagnostics if indicated (Covid19, Influenza, RSV, Chest XRay)
      5. HSV PCR from CSF, eye, Rectum and Vesicles if HSV risks (see below)
    3. Management (see expanded options below)
      1. Normal Saline Bolus for Sepsis, Dehydration or Hemodynamic instability
      2. IV Antibiotics
        1. Ceftazidime (or Cefotaxime if available) 50 mg/kg IV AND
        2. Ampicillin 50 mg/kg IV (or Vancomycin 15 mg/kg IV if NICU stay or known MRSA exposure)
      3. Acyclovir 20 mg/kg IV if HSV risks (see below)
      4. Tamiflu 3 mg/kg if Influenza positive and age >2 weeks
      5. Hospital admission until clinically well AND cultures and HSV PCR negative at 24 to 36 hours
  2. Age 22 to 28 days old: Careful evaluation of infants for Sepsis
    1. See Step-By-Step Protocol for Febrile Infants
    2. Perform a full Sepsis work-up unless exam, history and decision rules are completely reassuring
    3. Labs
      1. See Labs and Imaging below
      2. CBC with differential, Urinalysis with microscopic exam, Blood Culture
      3. Also obtain Procalcitonin (PCT), C-Reactive Protein (CRP)
      4. Respiratory diagnostics if indicated (Covid19, Influenza, RSV, Chest XRay)
      5. HSV PCR from CSF, eye, Rectum and Vesicles if HSV risks (see below)
    4. Positive Urinalysis
      1. Send Urine Culture
      2. Treat as Urinary Tract Infection with IV Antibiotics
      3. Disposition based on inflammatory marker results
    5. Management: Positive inflammatory markers (see PCT, CRP, ANC under labs below)
      1. Perform Lumbar Puncture
      2. Confirm Blood Cultures sent (as well as Urine Culture if positive Urinalysis)
      3. Normal Saline Bolus for Sepsis, Dehydration or Hemodynamic instability
      4. IV Antibiotics (see expanded options below)
        1. Meningitis: Ampicillin 75 mg/kg and Ceftazidime (or Cefotaxime if available) 50 mg/kg IV
        2. Non-Meningitis: Ceftriaxone 50 mg/kg IV
      5. Acyclovir 20 mg/kg if HSV risks (see below)
      6. Tamiflu 3 mg/kg if Influenza positive
      7. Hospital admission until clinically well AND cultures and HSV PCR negative at 24 to 36 hours
    6. Management: Negative inflammatory markers
      1. Lumbar Puncture positive (>18 WBCs, PMNs present) or uninterpretable (e.g. Traumatic LP)
        1. Administer IV Antibiotics and observe in hospital per inflammatory protocol above
      2. Lumbar Puncture not performed
        1. Observe in hospital until clinically well AND cultures and HSV PCR negative at 24 to 36 hours
        2. Consider IV Antibiotics (see regimen above) while awaiting test results
      3. Lumbar Puncture performed and negative (<=18 WBCs and no PMNs)
        1. Disposition based on Shared Decision Making with family
        2. Option 1: Consider IV Antibiotics and observe in hospital for 24 to 36 hours
        3. Option 2: Administer IV Antibiotics and discharge home and follow-up within 24 hours
  3. Age 29 to 60 days old: Careful evaluation of infants for Sepsis
    1. Perform a full Sepsis work-up unless exam, history and decision rules are completely reassuring
    2. Labs
      1. See Labs and Imaging below
      2. CBC with differential, Urinalysis with microscopic exam, Blood Culture
      3. Also obtain Procalcitonin (PCT), C-Reactive Protein (CRP)
      4. Respiratory diagnostics if indicated (Covid19, Influenza, RSV, Chest XRay)
      5. HSV PCR from CSF, eye, Rectum and Vesicles if HSV risks (see below)
    3. Management: Positive inflammatory markers (see PCT, CRP, ANC under labs below)
      1. Normal Saline Bolus for Sepsis, Dehydration or Hemodynamic instability
      2. Confirm Blood Cultures sent (as well as Urine Culture if positive Urinalysis)
      3. Consider Lumbar Puncture
      4. Lumbar Puncture positive (>9 WBCs, PMNs present)
        1. Administer IV Antibiotics for Meningitis (see below) and observe in hospital
      5. Lumbar Puncture not performed or uninterpretable (e.g. Traumatic LP)
        1. Administer IV Antibiotics
        2. Disposition based on Shared Decision Making with family
          1. Option 1: Observe in hospital for 24 to 36 hours
          2. Option 2: Discharge home and follow-up within 24 hours
      6. Lumbar Puncture performed and negative (<=9 WBCs and no PMNs)
        1. Administer IV Antibiotics or Oral Antibiotics
        2. Disposition and Antibiotic route based on Shared Decision Making with family
          1. Option 1: Observe in hospital for 24 to 36 hours
          2. Option 2: Discharge home and follow-up within 24 hours
    4. Positive Urinalysis in an otherwise well appearing infant with normal inflammatory markers
      1. Send Urine Culture
      2. No Lumbar Puncture needed
      3. Treat as Urinary Tract Infection with oral Antibiotics
      4. Recheck in 24 hours
    5. Antibiotic Regimens (see expanded options below)
      1. IV Antibiotics (indicated in positive inflammatory markers)
        1. Ceftriaxone 50 mg/kg IV (100 mg/kg IV if Meningitis suspected)
        2. Add Vancomycin 15 mg/kg IV if hemodynamic instability OR Gram Positive Cocci on CSF Gram Stain
      2. Oral Antibiotic (indicated in Urinary Tract Infection OR positive inflammatory markers AND negative CSF)
        1. Cephalexin (Keflex) 50 to 100 mg/kg/day divided four times daily OR
        2. Cefixime (Suprax) 8 mg/kg once daily
      3. Other medications
        1. Acyclovir 20 mg/kg IV if HSV risks (see below)
        2. Tamiflu 3 mg/kg if Influenza positive
    6. Other evaluation criteria (decision rules)
      1. Laboratory Score for Febrile Infants
      2. Rochester Criteria for Febrile Infant 0 to 60 days
      3. Philadelphia Criteria for Febrile Infant 29-60 days
      4. Milwaukee Criteria for Febrile Infant 28-56 days
      5. Boston Criteria for Febrile Infant 28-89 days
  4. Age 60 to 90 days
    1. Sick appearing infants
      1. Perform full Neonatal Sepsis evaluation (higher rate of bacteremia or Meningitis)
    2. Well appearing infants with fever >39 C
      1. Consider inflammatory markers, Urinalysis and Blood Culture
      2. Consider empiric Ceftriaxone dose and 24 hour follow-up
    3. Well appearing infants with fever <39 C
      1. Perform Urinalysis
        1. If Urinalysis positive, obtain Blood Cultures and inflammatory markers
  5. References
    1. Claudius and Drapkin in Swadron (2023) EM:Rap 23(6): 11-4
    2. Pantell (2021) Pediatrics 148(2): e2021052228 +PMID:34281996 [PubMed]

V. Approach: Modifications To Protocol

  1. Toxic appearing infant under age 3 months
    1. See Toxic Findings Suggestive of Occult Bacteremia
    2. Treat per Neonatal Sepsis protocol or Pediatric Sepsis protocol
  2. RSV Bronchiolitis
    1. Age <30 days
      1. Admit for observation of apnea AND
      2. Perform Neonatal Sepsis work-up with labs (Lumbar Puncture is a clinical decision at this age with RSV)
    2. Age 30-60 days
      1. Admit all infants under age 60 days for observation of apnea
      2. Perform Neonatal Sepsis evaluation if indicated
    3. Age 60 days
      1. Non-toxic febrile infants at 60-90 days with Bronchiolitis do not need bacteremia work-up
      2. Blood Cultures and Lumbar Puncture are not needed
      3. Urinalysis and Urine Culture should still be performed (5% co-Incidence of UTI)
      4. Ralston (2011) Arch Pediatr Adolesc Med 165(10):951-6 [PubMed]

VI. Signs

  1. See Toxic Findings Suggestive of Occult Bacteremia

VII. Labs

  1. See Fever Without Focus Labs
  2. CBC with differential
    1. Positive inflammatory marker if Absolute Neutrophil Count (ANC) >4000 cells/mm3
  3. Procalcitonin (PCT)
    1. Positive inflammatory marker if >0.5 ng/ml
    2. When Procalcitonin is unavailable or pending, fever > 101.3 F (38.5 C) may be used as inflammatory marker
  4. C-Reactive Protein (CRP)
    1. Positive inflammatory marker if >20 mg/L
  5. Blood Culture (one set)
  6. Urinalysis with microscopic exam
    1. Positive if any Leukocyte esterase present OR Urine White Blood Cells (WBC) >10 cells/mm3
  7. Urine Culture
    1. Send in all febrile infants <=21 days or if positive Urinalysis
  8. Lumbar Puncture
    1. Indications
      1. All febrile infants age <21 days old
      2. Febrile infants age 21 to 28 days old
      3. Optional in febrile infants age 29 to 60 days
    2. Positive criteria
      1. Any Neutrophils (PMNs) seen on grams stain OR
      2. White Blood Cells >18 cells in age <28 days (or >9 cells in age 29 to 60 days)
  9. Basic Metabolic Panel
    1. Indicated in age <21 days
  10. Total Serum Bilirubin
    1. Indicated in age <21 days
  11. Respiratory infection labs as indicated for respiratory symptoms (or at time of outbreak)
    1. Influenza Swab
    2. Covid19 nasal swab
    3. Respiratory Syncytial Virus (RSV) nasal swab
  12. Herpes Simplex Virus (HSV)
    1. Indications
      1. Maternal Genital Herpes symptoms within 1 week of delivery
      2. Household HSV contact
      3. Cutaneous Vesicles
      4. Seizure
      5. Hypothermia
      6. Ill appearing infant
      7. Sepsis-like syndrome
      8. Elevated Liver Function Tests
      9. Coagulopathy
      10. CSF Pleocytosis with negative Gram Stain
    2. HSV Labs
      1. CSF Herpes Simplex Virus PCR
      2. Herpes Simplex Virus PCR and culture swabs from eye, Rectum (and Vesicle if present)
      3. Liver Function Tests

VIII. Imaging

  1. Chest XRay
    1. Indicated for fever with respiratory symptoms
    2. Chest XRay is NOT required in all febrile infants

IX. Risk Factors: High Risk, Red Flag Indicators - Findings Suggestive of Occult Bacteremia

  1. Age <13 days
  2. History of exposure to serious infection
  3. Fever > 39.5 to 40.0 degrees Celsius
  4. White Blood Cell Count
    1. Markers
      1. Leukopenia <5,000
        1. Serious Bacterial Infection risk PPV >44%
        2. Sepsis risk increased at <4.1k
      2. Leukocytosis >15,000
        1. Serious Bacterial Infection risk PPV >44%
        2. Sepsis risk increased at >20k
      3. Absolute Neutrophil Count (ANC) > 10,000
        1. Serious Bacterial Infection risk PPV >71%
      4. References
        1. Bressan (2010) Pediatr Infect Dis J 29(3): 227-32 [PubMed]
    2. Precautions
      1. Normal WBC Count does not rule-out Meningitis
        1. Bonsu (2003) Ann Emerg Med 41:206-14 [PubMed]
      2. Normal WBC Count does not rule-out bacteremia
        1. Bonsu (2003) Ann Emerg Med 42:216-25 [PubMed]
  5. Inflammatory Markers (CRP, Procalcitonin)
    1. See CRP Evaluation for Febrile Infants Age 1 to 3 months
    2. See Procalcitonin Evaluation for Febrile Infants Age 1 to 3 months
  6. Urinalysis positive
    1. Positive Findings
      1. Leukocyte esterase positive
      2. Nitrite positive
      3. White Blood Cells >5 cells/hpf on spun sample
    2. Precaution
      1. Catheterized urine or suprapubic aspirate for all samples
        1. Bag urine has 85% False Positive Rate
        2. Fineell (2011) Pediatrics 128(3):e749-70 [PubMed]
      2. Urine Culture all samples
        1. Urine dipstick False Negative Rate: 12%
        2. Gorelick (1999) Pediatrics 104(5): e54 [PubMed]
  7. References
    1. Bachur (2001) Pediatrics 108(2):311-16 [PubMed]

X. Risk Factors: Low Risk Indicators

  1. Low Risk Stratification protocol (previously healthy infants <60 days old)
    1. Precautions
      1. Study focused on infants younger than 60 days old with many exclusion criteria
    2. Low Risk Criteria (all must be present)
      1. Urinalysis negative
      2. Absolute Neutrophil Count (ANC) <4000/ul
      3. Procalcitonin <1.71 ng/ml
    3. Interpretation
      1. All 3 negative criteria was reassuring for lack of serious Bacterial Infection
      2. Identified 98.8% of ill children requiring additional Sepsis workup
    4. References
      1. Claudius and Behar in Herbert (2019) EM:Rap 19(7): 7
      2. Kupperman (2019) JAMA Pediatr 173(4): 342-51 [PubMed]

XI. Management: Age <21 days old

  1. See Fever Without Focus for signs of toxicity
  2. Admit for assessment as for Neonatal Sepsis
  3. Perform labs and evaluation as above
  4. Normal Saline Bolus
    1. Indicated for Sepsis, Dehydration or hemodynamic instability
  5. Protocol: Antibiotics (use both Antibiotics)
    1. Antibiotic 1: Cephalosporin or Gentamicin
      1. Do not use Ceftriaxone in under age 1 month (due to Kernicterus risk)
      2. Cefotaxime 50 mg/kg IV every 8 hours (shortage in 2021 limits use) OR
      3. Ceftazidime 50 mg/kg IV every 8 hours OR
      4. Gentamicin 2.5 mg/kg IV or IM every 8 hours (adjust based on serum levels)
    2. Antibiotic 2: Ampicillin or Vancomycin
      1. Ampicillin 50 mg/kg IV or IM every 6 hours (preferred in most cases) OR
      2. Vancomycin 15 mg/kg IV instead IF NICU stay, known MRSA exposure or Streptococcal Pneumoniae Meningitis
  6. Other antimicrobials
    1. Acyclovir 20 mg/kg IV if HSV risks (see labs above)
    2. Tamiflu 3 mg/kg if Influenza positive and age >2 weeks
  7. Disposition
    1. Hospital admission until clinically well AND cultures and HSV PCR negative at 24 to 36 hours

XII. Management: Age 22 to 28 days old

  1. See Step-By-Step Protocol for Febrile Infants
  2. Perform lab evaluation as above
  3. Perform a full Sepsis work-up unless exam, history and decision rules are completely reassuring
  4. Positive Urinalysis
    1. Send Urine Culture
    2. Treat as Urinary Tract Infection with IV Antibiotics
    3. Disposition based on inflammatory marker results
  5. Management: Positive inflammatory markers (see PCT, CRP, ANC under labs below)
    1. Perform Lumbar Puncture
    2. Confirm Blood Cultures sent (as well as Urine Culture if positive Urinalysis)
    3. Normal Saline Bolus for Sepsis, Dehydration or Hemodynamic instability
    4. IV Antibiotics
      1. Meningitis: Ampicillin 75 mg/kg and Ceftazidime 50 mg/kg IV
      2. Non-Meningitis: Ceftriaxone 50 mg/kg IV
    5. Acyclovir 20 mg/kg if HSV risks (see below)
    6. Tamiflu 3 mg/kg if Influenza positive
    7. Hospital admission until clinically well AND cultures and HSV PCR negative at 24 to 36 hours
  6. Management: Negative inflammatory markers
    1. Lumbar Puncture positive (>18 WBCs, PMNs present) or uninterpretable (e.g. Traumatic LP)
      1. Administer IV Antibiotics and observe in hospital per inflammatory protocol above
    2. Lumbar Puncture not performed
      1. Observe in hospital until clinically well AND cultures and HSV PCR negative at 24 to 36 hours
      2. Consider IV Antibiotics (see regimen above) while awaiting test results
    3. Lumbar Puncture performed and negative (<=18 WBCs and no PMNs)
      1. Disposition based on Shared Decision Making with family
      2. Option 1: Consider IV Antibiotics and observe in hospital for 24 to 36 hours
      3. Option 2: Administer IV Antibiotics and discharge home and follow-up within 24 hours (see criteria below)

XIII. Management: Age 29 to 60 days old

  1. Perform Labs as above
  2. Perform a full Sepsis work-up unless exam, history and decision rules are completely reassuring
  3. Management: Positive inflammatory markers (see PCT, CRP, ANC under labs below)
    1. Normal Saline Bolus for Sepsis, Dehydration or Hemodynamic instability
    2. Confirm Blood Cultures sent (as well as Urine Culture if positive Urinalysis)
    3. Consider Lumbar Puncture
    4. Lumbar Puncture positive (>9 WBCs, PMNs present)
      1. Administer IV Antibiotics for Meningitis (see below) and observe in hospital
    5. Lumbar Puncture not performed or uninterpretable (e.g. Traumatic LP)
      1. Administer IV Antibiotics
      2. Disposition based on Shared Decision Making with family
        1. Option 1: Observe in hospital for 24 to 36 hours
        2. Option 2: Discharge home and follow-up within 24 hours (see criteria below)
    6. Lumbar Puncture performed and negative (<=9 WBCs and no PMNs)
      1. Administer IV Antibiotics or Oral Antibiotics
      2. Disposition and Antibiotic route based on Shared Decision Making with family
        1. Option 1: Observe in hospital for 24 to 36 hours
        2. Option 2: Discharge home and follow-up within 24 hours (see criteria below)
  4. Positive Urinalysis in an otherwise well appearing infant with normal inflammatory markers
    1. Send Urine Culture
    2. No Lumbar Puncture needed
    3. Treat as Urinary Tract Infection with oral Antibiotics
    4. Recheck in 24 hours
  5. Antibiotic Regimens
    1. IV Antibiotics (indicated in positive inflammatory markers)
      1. See Neonatal SepsisAntibiotic protocol
      2. Meningitis not suspected
        1. Ceftriaxone 50 to 75 mg/kg/day IV or IM divided every 12 to 24 hours OR
        2. Cefotaxime 75 to 200 mg/kg/day IV or IM divided every 6 to 8 hours
      3. Meningitis suspected
        1. Ceftriaxone 100 mg/kg IV or IM divided every 12 to 24 hours (max: 4 g per 24 hours) AND
        2. Vancomycin 15 mg/kg IV if Streptococcal Pneumoniae Meningitis suspected
      4. Vancomycin indications
        1. Hemodynamic instability
        2. Gram Positive Cocci on CSF Gram Stain
      5. Listeria or Enterococcus is a concern
        1. Add Ampicillin 50 mg/kg every 6 hours IV or IM
    2. Oral Antibiotic
      1. Indicated in Urinary Tract Infection (OR positive inflammatory markers AND negative CSF)
      2. Cephalexin (Keflex) 50 to 100 mg/kg/day divided four times daily OR
      3. Cefixime (Suprax) 8 mg/kg once daily
    3. Other medications
      1. Acyclovir 20 mg/kg IV if HSV risks (see below)
      2. Tamiflu 3 mg/kg if Influenza positive

XIV. Management: Criteria for home observation (24 hour follow-up)

  1. Must have non-toxic appearance and be at low risk of Sepsis
    1. See Toxic Findings Suggestive of Occult Bacteremia
    2. See risk factors above
    3. See Fever Without Focus for signs of toxicity
    4. Term infant without chronic disease or hospitalizations
    5. See Laboratory Score for Febrile Infants
    6. See Rochester Criteria for Febrile Infant 0 to 60 days
    7. See Philadelphia Criteria for Febrile Infant 29-60 days
    8. See Milwaukee Criteria for Febrile Infant 28-56 days
    9. See Boston Criteria for Febrile Infant 28-89 days
  2. Must be reliable for follow-up
    1. Reliable care takers
    2. Transportation and telephone available
    3. Willingness to return in 24 hours

XV. References

  1. Claudius and Behar in Herbert (2019) EM:Rap 19(7): 7
  2. Herman (2015) Crit Dec Emerg Med 29(12):14-19
  3. Hendrickson (2022) Fairview Emergency Department Update, attended 3/15/2022, Wyoming, MN
  4. Latessa (2012) AAFP Board Review Express, San Jose
  5. Wang and Claudius in Herbert (2013) EM:Rap 13(6): 1-2
  6. Baraff (1993) Pediatrics 92:1-12 [PubMed]
  7. Baraff (2000) Ann Emerg Med 36:602-14 [PubMed]
  8. Hamilton (2013) Am Fam Physician 87(4): 254-60 [PubMed]
  9. Hamilton (2020) Am Fam Physician 101(12): 721-9 [PubMed]
  10. Luszczak (2001) Am Fam Physician 64(7):1219-26 [PubMed]
  11. Pantell (2021) Pediatrics 148(2): e2021052228 +PMID:34281996 [PubMed]
  12. Sur (2007) Am Fam Physician 75:1805-11 [PubMed]

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