1. Assistant Clinical Professor
Neonatal Fever
Shabnam Zargar, MD, FAAP
Assistant Clinical Professor
Pediatrics
UCR School of Medicine

2. Neonatal Fever
A 15 day old infant presents to the ED with a temperature of 38.4 degrees Celsius (101.4 Fahrenheit). What to do next and why?

3. Neonatal fever
What is neonatal fever? Temperature of 38 degrees Celsius (100.4 Fahrenheit) in infants 0-28 days of life. Rectal temperature recommended
Some sources consider neonate <30 days old – most pediatric sources use <30 days, Cincinnati uses 28 days

4. Neonatal Fever
Why is neonatal fever important? Febrile neonates are at high risk for serious infection (SI) or serious bacterial infection (SBI) because of increased susceptibility to infections, difficulty with clinical examination, and poor outcomes if not diagnosed or treated properly
A neonate cannot tell you what is wrong

5. Neonatal Fever Differential Diagnoses: Meningitis bacterial or viral
Bacterial – GBS, E. coli, Listeria
Viral – Enterovirus
HSV infections
localized or disseminated infections
UTI
E. coli, Enterococcus
Bacteremia
Sepsis
Cellulitis
Abscess
Osteomyelitis
Septic arthritis
Viral
Localized HSV – encephalitis w/wo skin involvement or skin, eye, and mouth
Disseminated – hepatitis, pneumonitis, or DIC w/wo encephalitis or skin disease

6. Neonatal Fever
Most common etiology Viral illness Viral Bacterial etiologies: Most common – UTI UTI Followed by: Meningitis Bacteremia/Sepsis Sepsis or bacteremia Abscess or cellulitis Pneumonia Meningitis Approximately 12%-28% of neonates presenting to a pediatric ED with fever have a SBI - bacteremia, gastroenteritis, cellulitis, osteomyelitis, septic arthritis, meningitis, pneumonia, and UTI (Cincinnati)
Neonates with viral etiology are less likely to have a SBI
If viral illness, 4.2% have SBI vs 12.3% without viral illness

7. Neonatal Fever History to obtain:
Febrile infants may have few symptoms to guide diagnosis and management
History to obtain:
Fever? How high?
How was temperature measured?
Last anti-pyretic use?
Change in feeding?
Irritability or lethargy?
Seizures?
Change in cry?
URI symptoms?
Difficulty breathing?
Swelling of joints or skin changes?
Sick contacts?
Vomiting or diarrhea?
Skin changes – rashes/vesicles/jaundice

8. Neonatal Fever Physical exam Gen: Mentation?
HEENT: Anterior fontanelle – bulging? Eyes – Cellulitis/conjunctivitis? Ears – otitis? Nose – congestion? Rhinorrhea? Throat – weak/high pitched cry? Cough?
Neck: Swelling? Neck stiffness is a sign in older children
Lungs: Retractions? Crackles? Ronchi?
CVS: Murmur? Tachycardia? Capillary refill? Pulses?
Abdomen: Omphalitis?
GU: Circumcised?
Skin: Cellulitis/Abscess? Rash?
MSK: Joint swelling?
Neuro: Mentation? Irritable? Lethargic?
Omphalitis – polymicrobial – S. aureus, GAS, E. coli, K. pneumoniae, Proteus mirabilis
Brudzinski sign – flexion of the neck elicits reflex flexion of the hips
Kernig sign – extension of a flexed knee is painful

9. Neonatal Fever Diagnosis Laboratory: Full sepsis workup
CBC with manual differential
Blood culture
UA with microanalysis (urethral catheterization)
Urine Culture
CSF studies – tube 1 culture, tube 2 protein and glucose, tube 3 cell count and differential,
tube 4 – HSV PCR if HSV encephalomengitis suggested
If CSF pleocytosis, add enterovirus PCR
CXR if symptomatic
Stool culture if diarrhea present
*Ok to delay LP if patient unstable, do administer antibiotics!
*Full septic workup still recommended in neonates with
symptoms of bronchiolitis
CXR recs differ from AAFP

10. Neonatal Fever Values CBC with manual differential:
Normal WBC 5,000-15,000 per mm3
WBC < 5,000 or >15,000 per mm3 or ANC >10,000 per mm3 have increased risk of SBI
CSF:
Low risk of meningitis: <20WBC/mm3
High risk of meningitis: >20WBC/mm3
Other values: High protein >120mg/dL and low glucose <40mg/dL
Urinalysis:
WBC < 10/mm3, negative LE and nitrites
Harriet Lane has values

11. Neonatal Fever Management Admit to inpatient pending culture results
IV antibiotics to cover common organisms – empirical treatment should be given immediately after cultures obtained
Ampicillin and gentamicin
Ampicillin and 3rd generation cephalosporin
-Cefotaxime preferred over ceftriaxone
*All neonates should be given a single dose of ampicillin and cefotaxime immediately after cultures are obtained
IV antiviral
Acyclovir should be started on all neonates who have pending CSF HSV PCR studies
Clinical prediction models have not been able to accurately predict SBIs in neonates so common practice remains for hospitalization for sepsis evaluation and IV antibiotics (Fielding-Singh et al.)

12. Neonatal fever Antibiotics Ampicillin Gentamicin Cefotaxime
covers Enterococcus and Listeria, also Streptococcus/gram positives
Gentamicin
covers gram negatives, crosses blood brain barrier
Cefotaxime
covers gram negatives (rising resistance of E. coli to Ampicillin), crosses blood brain barrier

13. Neonatal Fever
All febrile neonates ≤ 28 days of age should be hospitalized, undergo a full sepsis evaluation, and receive empirical IV antibiotics

14. Neonatal fever
Pre-treated CSF: Can add real time PCR and DNA sequencing for bacterial rRNA if pleocytosis is present and there is a concern for meningitis

15. Neonatal Fever HSV in neonates Comprehensive testing required
Surface swabs sent for HSV culture from
nasopharynx, conjunctivae, and anus
CSF for HSV PCR
Blood for HSV PCR
Vesicle fluid for HSV PCR – if rash present
CBC with differential, BUN, creatinine,
AST and ALT
Nelson Textbook of Pediatrics: Expert Consult

16. Neonatal Fever
HSV in neonates Greatest risk in neonates born vaginally to mothers with risk factors for primary maternal HSV infection Clinical features: severe illness, hypothermia, lethargy, seizures, HSM, postnatal HSV contact, vesicular rash, conjunctivitis, interstitial pneumonitis Laboratory features: Thrombocytopenia, elevated transaminases, CSF pleocytosis >20 WBC/mm3 with negative gram stain *If suspicion for HSV infection or HSV PCR performed on CSF, begin acyclovir with empiric antibiotics
What are some of the risk factors? Mom’s sexual partners have history of oral or genital HSV, new sexual partner in pregnancy, sores in vagina during pregnancy, urinary retention, hx of frequent yeast infections, receipt of oral sex during last half of pregnancy from partner with hx of cold sores
Merck Manual Professional Version

17. Neonatal Fever How long to admit for?
Standard length of hospitalization: 48 hours – “48 hour rule out sepsis”
Studies are being performed to determine
if 48 hours of hospitalization is really
needed
Recent studies have also looked at low risk
criteria for treating febrile neonates less
conservatively but concluded that low risk
criteria are not sufficiently reliable to exclude
SBIs in febrile neonates
Standard has been to admit for 48 hours – why? Because at 48 hours, there is greatest chance of negative cultures being truly negative. Some centers changing to 36 hours and even 24 hours.

18. Neonatal Fever
One study from Hospital Pediatrics (Fielding-Singh et al.): Objective: To determine the risk of a positive, pathogenic bacterial culture of blood or CSF in infants ≤ 30 days beyond 24 hours after collection Methods: retrospective review of 1,145 infants ≤ 30 days with blood or CSF cultures drawn at Santa Clara Valley Medical Center in San Jose, CA from High risk infants had WBC <5,000 or >15,000 per microliter, bands >1,500 per microliter, or abnormal UA Results: 1,876 blood and CSF cultures were identified. 79% were hospitalized and of those hospitalized, 45% were for fever without a source. 2.7% had pathogenic cultures and 0.5% had a time to notification >24 hours (not statistically significant), of those 0.5%, all had fever without source and high-risk criteria. No low-risk criteria patient had a time to notification >24 hours. 1.8% of high risk patients had growth hours. Conclusion: Low-risk infants hospitalized for fever without source may not need hospitalization for 48 hours to rule out bacteremia or meningitis
Non-ICU patients. Time to notification = time from sample collection to notification of medical staff. Time to notification for urine not available because medical staff not contacted directly with positive UAs. Those with TTN >24 hours had E. coli, Enterococcus, GBS and S. aureus bacteremia. Low risk = well-appearing, previously healthy, no focal infection, normal UA and WBC, nml CXR and stool smear

19. Neonatal fever
Study continued: Mean and median time to notification 24.5 ± 17.1 and 19 hours for pathogens and 45.3 ± 30.7 and 35.8 hours for contaminants, respectively

20. Neonatal Fever
Previous studies: Time to positivity of blood and CSF cultures in neonates suggest that 48 hours is necessary to identify >95% of cases, however, these studies included infants in the ICU where CoNS and yeast cultured from central lines take time to grow (Fielding et al.)

21. Neonatal Fever
Approximately 90% of bacterial pathogens are identified within the first 24 hours of incubation (Byington et al.) Infants 0-6 months of age: Blood cultures: Mean time to positivity for true pathogens is ~17.5 hours Urine and CSF: Median time to positivity are 16 and 18 hours, respectively

22. Seattle Children’s recommends this
Neonatal Fever
Consider discharge at 24 hours if bacterial cultures negative and viral studies positive (excluding HSV) AND well-appearing
Patients with bronchiolitis or other viral infections are at lower risk of SBI
Seattle Children’s recommends this

23. Neonatal Fever Discharge criteria: Well-appearing Tolerating PO
Follow up available within hours
Family and primary care team agree with plan
Cultures negative
What do you think would be some discharge criteria?

24. Neonatal Fever
If a neonate presents with fever to your clinic -Send to the ED If you receive a call from a mom stating her neonate has a fever If you are working in the ED and have a neonate with fever -Perform full septic workup, give first dose of ampicillin and cefotaxime, and admit to inpatient If you are the admitting inpatient team – continue/begin empirical antibiotics, making sure urine, blood, and CSF cultures have been drawn (if LP not successful and patient appears meningitic – do not delay antibiotics), and observe 48 hours pending cultures
real time PCR and DNA sequencing for bacterial rRNA

25. Neonatal Fever
Side note: Neonates with meningitis need to be admitted to a hospital with pediatrics ID and PICU -Complications – seizures, empyema, elevated ICP -BAER and ophthalmology exam

26. Neonatal Fever
Possible QI project? Develop a standardization pathway of management of neonatal fever in our institution based on clinical evidence Standardization improves medical care!
Discuss neonatal age as being less than 28 or 30 days and decide length of hospitalization

27. References
Bishop, Julianne, and S. Heath Ackley. Clinical Standard Pathway: Neonatal Fever. Project Owners, Aug Web. 20 July Byington, Carrie L., F. Rene Enriquez, Charles Hoff, Richard Tuohy, E. William Taggart, David R. Hillyard, Karen C. Carroll, and John C. Christenson. "Serious Bacterial Infections in Febrile Infants 1 to 90 Days Old With and Without Viral Infections." Pediatrics (2004): Caserta, Mary T. "Neonatal Herpes Simplex Virus (HSV) Infection - Pediatrics." Merck Manuals Professional Edition. Merck Sharp & Dohme Corp, May Accessed 24 July Cincinnati Children's Hospital Medical Center. Evidence-based care guideline for fever of uncertain source in infants 60 days of age or less. October 27, Accessed July 20, 2015 Fielding-Singh, Vikram, David K. Hong, Stephen J. Harris, John R. Hamilton, and Alan R. Schroeder. "Ruling Out Bacteremia and Bacterial Meningitis in Infants Less Than One Month Of Age: Is 48 Hours of Hospitalization Necessary?" Hospital Pediatrics 3.4 (2013): Web. Hamilton, Jennifer L., and Sony P. John. "Evaluation of Fever in Infants and Young Children." American Family Physician (2013): Accessed July 20, Kliegman, Robert M., Bonita M.D. Stanton, Joseph St. Geme, and Nina F. Schor. Nelson's Textbook of Pediatrics: Expert Consult. 20th ed. Philadelphia: Elsevier, Jain, Shabnam, John Cheng, Elizabeth R. Alpern, Cary Thurm, Lisa Schroeder, Kelly Black, Angela M. Ellison, Kimberly Stone, and Evaline A. Alessandrini. "Management of Febrile Neonates in US Pediatric Emergency Departments." Pediatrics (2014):