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Neonatal Fever

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?

Neonatal fever

What is neonatal fever?

Temperature of 38 degrees Celsius (100.4 Fahrenheit) in infants 0-28 days of life.

Rectal temperaturerecommended

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

Neonatal Fever

Differential Diagnoses:

Meningitis bacterial or viral

Bacterial – GBS, E. coli, Listeria Viral – Enterovirus

HSV infections localized or disseminated infectionsUTI E. coli, EnterococcusBacteremiaSepsisCellulitisAbscessOsteomyelitisSeptic arthritisViral

Neonatal Fever

Most common etiologyViral illness Viral

Bacterial etiologies:Most common – UTI UTI

Followed by:Meningitis Bacteremia/SepsisSepsis or bacteremia Abscess or cellulitisPneumonia 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)

Neonatal Fever

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?

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?

Neonatal Fever

Diagnosis

Laboratory: Full sepsis workupCBC with manual differentialBlood cultureUA with microanalysis (urethral catheterization)Urine CultureCSF 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 symptomaticStool 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

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

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 gentamicinAmpicillin 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.)

Neonatal fever

Antibiotics

Ampicillin 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

Neonatal Fever

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

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

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

Neonatal Fever

HSV in neonatesGreatest 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

Merck Manual Professional Version

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 riskcriteria for treating febrile neonates less conservatively but concluded that low risk criteria are not sufficiently reliable to excludeSBIs in febrile neonates

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 1999-2010. 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 24-48 hours.

Conclusion: Low-risk infants hospitalized for fever without source may not need hospitalization for 48 hours to rule out bacteremia or meningitis

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

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.)

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

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

Neonatal Fever

Discharge criteria:

Well-appearingTolerating POFollow up available within 48-72 hoursFamily and primary care team agree with

planCultures negative

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-Send to the ED

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

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

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!

References

Bishop, Julianne, and S. Heath Ackley. Clinical Standard Pathway: Neonatal Fever. Project Owners, Aug. 2013. Web. 20 July 2015. https://www.seattlechildrens.org/pdf/neonatal-fever-learning-module.pdf.

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 113.6 (2004): 1662-666.

Caserta, Mary T. "Neonatal Herpes Simplex Virus (HSV) Infection - Pediatrics." Merck Manuals Professional Edition. Merck Sharp & Dohme Corp, May 2013. http://www.merckmanuals.com/professional/pediatrics/infections-in-neonates/neonatal-herpes-simplex-virus-hsv-infection. Accessed 24 July 2015.

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, 2010. http://www.cincinnatichildrens.org/svc/alpha/h/health-policy/ev-based/default.htm. 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): 355-61. Web.

Hamilton, Jennifer L., and Sony P. John. "Evaluation of Fever in Infants and Young Children." American Family Physician (2013): http://www.aafp.org/afp/2013/0215/p254.html. Accessed July 20, 2015.

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, 2016.

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 133.2 (2014): 187-95.