1. Fever National Pediatric Nighttime Curriculum
Written by Debbie Sakai, M.D.
Institution: Lucile Packard Children’s Hospital

2. Case 1
4-month-old well-appearing girl admitted for croup and respiratory distress. Develops fever to 39.1.
What additional evaluation would you do at this point?
Teacher’s Guide:
Most cases of croup are secondary to viral infections especially parainfluenza.
Mild-moderate disease is usually caused by adenovirus, rhinovirus, RSV.
Severe disease is usually caused by influenza (especially type A), parainfluenza 3, and measles.
A secondary bacterial infection is less likely in a well-appearing child.
Since croup is a recognizable viral syndrome and the patient is well-appearing, no additional workup is necessary.
However, if the patient only had an upper respiratory infection, consider obtaining urinalysis/urine culture to evaluate for concomitant UTI.

3. Case 2
12-year old boy with AML, in induction, admitted for febrile neutropenia. He had just received his first dose of ceftazidime and vancomycin when he developed another fever to 38.5, chills, and new dizziness shortly after receiving the antibiotics.
What would be the next steps in this patient’s management?
Teacher’s Guide:
The history is concerning for acute decompensation from bacterial lysis after initiation of antibiotic therapy.
Vital signs should be repeated and patient should be evaluated for signs of shock.
Patient should receive NS bolus to help with acute symptoms.
Strongly consider calling a Rapid Response for additional assistance.

4. Objectives
To determine which patients are at high risk of developing sepsis.
To assess patient with fever.
To initiate empiric therapy.

5. Objectives
To determine which patients are at high risk of developing sepsis.
To assess patient with fever.
To initiate empiric therapy. 5

6. Which patients are high-risk for sepsis?
Neonates
Transplant recipients
Bone marrow
Solid organ
Oncology patients
Undergoing therapy, mucositis, central line
Most chemotherapy: nadir ~ 10 days after rx
Asplenic patients, including sickle cell
Teacher’s Guide:
Patients at high-risk for developing sepsis include neonates, transplant recipients, oncology patients (most chemotherapy agents result in wbc nadir/neutropenia approximately 10 days after therapy), and asplenic patients including sickle cell patients

7. Definition of fever
38.0
Neonates (< 12 months)
Any immunocompromised patient
Including transplant patients, patients with immunodeficiencies, oncology patients (sustained ≥38 x 1 hour)
38.5
All other patients
These are general guidelines, individual patients/services may have different parameters
Teacher’s Guide:
The definition of fever varies among different clinical services.
For patients at higher risk of sepsis, the threshold for fever tends to be lower.
For example, neonates and transplant (especially BMT) patients and those who have immunodeficiencies, the cutoff is 38.0 C.
For otherwise healthy children who are non-toxic in appearance, the threshold is often 38.5.
However, these are general guidelines only and individual subspecialty services may have different parameters.

8. What etiologies cause fever?
Infectious
Inflammatory
Oncologic
Other: CNS dysfunction, drug fever
Life-threatening conditions
Teacher’s Guide:
Fever can arise from infectious, inflammatory, and oncology etiologies.
There are a few conditions that may be life-threatening that need to be readily identified.
Infection remain the most common cause of fevers in children. Less common sources of fevers include inflammatory and oncologic diseases.

9. Infectious Systemic Respiratory Abdominal Bone/joint infection
Bacteremia, sepsis, meningitis, endocarditis
Respiratory
URI, sinusitis, otitis media, pharyngitis, pneumonia, bronchiolitis
Abdominal
Urinary tract infection, abscess (liver, kidney, pelvis)
Bone/joint infection
Hardware infection
Central line, VP shunt, G-tube

10. Inflammatory Kawasaki disease Juvenile inflammatory arthritis Lupus
Inflammatory bowel disease
Henoch-Schonlein purpura
Teacher’s Guide:

11. Others CNS dysfunction Drug fever Teacher’s Guide:
Less likely causes of fever in children are CNS dysfunction/dysautonomia or drug fever. Generally other common causes need to be investigated and excluded before CNS dysfunction or drug fever can be diagnosed.

12. Life-threatening conditions
Sepsis, febrile neutropenia
Vital sign instability, poor-perfusion, may have altered mental status, disseminated intravascular coagulation
Hemophagocytic lymphohistiocytosis
Splenomegaly, bicytopenia, elevated ferritin, elevated triglycerides, low fibrinogen, hemophagocytosis, low/absent NK cell function, elevated soluble IL2 receptor
Malignant hyperthermia
Following administration of inhaled anesthetics or depolarizing neuromuscular blockers (succinylcholine), at-risk patients include those with myopathy
Muscle rigidity, rhabdomyolysis, acidosis, tachycardia

13. Objectives
To determine which patients are at high risk of developing sepsis.
To assess patient with fever.
To initiate empiric therapy. 13

14. Assessment Vital signs Repeat physical exam
Overall appearance (sick, toxic)
Central/peripheral lines
Incisions/wounds
VP shunt/tracheostomy/gastrostomy tube
Oral mucosa/perineal area for neutropenic patients
Perfusion
Call for help if concerning vital signs/exam
Fellow or attending
Rapid response team (RRT)/PICU
Teacher’s Guide:
The assessment should begin with a set of vital sign and repeat physical exam.
In particular, it is helpful to note the patient’s overall appearance (sick vs not sick) and perfusion.
In addition to the routine heart/lung/abdominal exam, evaluate potential sites of infection such as central/peripheral lines for erythema, tenderness to palpation especially along the track site for central lines, if there are symptoms when the line is accessed or flushed (chills, changes in vital signs).
Also re-evaluate any wounds or incisions, indwelling hardware such as VP shunts, tracheostomy, gastrostomy tubes.
In particular for immunocompromised/neutropenic patients, pay special attention to the oral mucosa and perineal area for any breakdown or signs of mucositis.
Unless previously discussed with the felllow/attending, do not perform a rectal exam on neutropenic patients (because of the risk of causing a tear that may result in bacterial translocation).
Instead, have the patient “bear down” and evaluate the rectal mucosa by external exam only.
Call for help for patients with concerning exam (fellow, attending, or RRT)

15. Laboratory evaluation
What would you do if the patient has hardware (VP shunt, tracheostomy, gastrostomy tube) or central line?
CBC with differential
Blood culture
CSF (tap VP shunt)
Teacher’s Guide:
For patients with indwelling hardware:
Obtain CBC with differential and blood culture.
Consider obtaining CSF by tapping the VP shunt.

16. Laboratory evaluation
What would you do if the patient has a high risk for sepsis?
Immunocompromised
Transplant recipient
Oncology patient
CBC with differential
Blood culture
Urinalysis and urine culture
Teacher’s Guide:
For patients at high risk for sepsis (immunocompromised/transplant recipient/oncology patient), obtain:
CBC with differential
Blood culture
Urinalysis and urine culture

17. Laboratory evaluation
What would you do for an infant ≤ 2 months of age?
CBC with differential
Blood culture
Catheterized urinalysis and urine culture
Lumbar puncture
Teacher’s Guide:
For infants ≤ 2 months of age obtain:
CBC with differential
Blood culture
Catheterized urinalysis and urine culture
Lumbar puncture

18. Laboratory evaluation
Who needs a urinalysis and urine culture?
Circumcised males < 6 months
Uncircumcised males < 1 year
Females < 2 years
Immunocompromised patients
Patients with history of UTI/pyelonephritis
Teacher’s Guide:
Urinalysis and urine culture for at risk patients:
Circumcised males < 6 months
Uncircumcised males < 1 year
Females < 2 years
Immunocompromised patients
Patients with history of UTI/pyelonephritis
In general, catheterized or clean-catch specimens are preferred (except in the oncology/BMT population).

19. Laboratory evaluation
Who needs a lumbar puncture?
Neonates ≤ 2 months
Ill-appearing
Altered mental status
What tests do you send?
Gram stain and culture
Cell count and differential
Protein and glucose
Extra tube for additional studies
Enteroviral PCR, HSV PCR, CA encephalitis project
Teacher’s Guide:
Lumbar puncture is recommended for neonates ≤ 2 months, patients who are toxic/ill-appearing or have altered mental status.
Studies include gram stain and culture, cell count with differential, protein, glucose, and extra tube (if possible) for additional studies depending on clinical suspicion.

20. Laboratory evaluation
Consider CRP, ESR
Consider PT/PTT, fibrinogen
Consider chest x-ray
Consider nasopharyngeal DFA
For immunosuppressed patients consider:
Viral PCR studies (ie CMV, EBV, HHV6)
Additional imaging (ie ultrasound, CT scan)
Teacher’s Guide:
Consider additional markers of inflammation and screening labs for DIC.
For patients with respiratory symptoms, consider CXR and nasopharyngeal DFA (if it will change your management).
For immunosuppressed patients, consider additional viral studies such as CMV, EBV, HHV6, etc or galactomannan (for fungus) or additional imaging (u/s, CT scan) to evaluate for abscesses or fungal infections (particularly for prolonged fevers).

21. Objectives
To determine which patients are at high risk of developing sepsis.
To assess patient with fever.
To initiate empiric therapy. 21

22. Treatment for non-high risk patients
May not need empiric antibiotics
Consider the following issues:
Is patient clinically stable?
Are the screening laboratory studies suggestive of infection?
Teacher’s Guide:
Not all patients will require empiric antibiotic therapy, especially those not at high-risk for sepsis.
Consider deferring antibiotics for non-high risk patients who are clinically stable and with reassuring labs studies.

23. Treatment for patients with central lines
Ceftriaxone
Vancomycin
Teacher’s Guide:
For patients with central lines, generally recommend empiric therapy for r/o sepsis with gram negative and gram positive coverage (ie ceftriaxone +/- vancomycin)

24. Treatment for neonates ≤ 2 months
If < 28 days old
Ampicillin AND cefotaxime OR
Ampicillin AND gentamicin
Consider acyclovir
If days old
Ceftriaxone ± Ampicillin OR Vancomycin
Until CSF results are known (cell count, protein, glucose), initiate therapy with meningitic dosing regimen
Teacher’s Guide:
For neonates <28 days, likely bacteria infections include E. Coli, Klebsiella, Group B Streptococus, Enterococcus, Enterobacter, and Listeria.
To cover these organisms, recommend initiating therapy with ampicillin (to cover Listeria and GBS) AND cefotaxime OR ampicillin AND gentamicin (to cover GNR).
Consider adding acyclovir for patients with concern for HSV infection.
For neonates days, S. pneumoniae becomes more common.
Initiate therapy with ceftriaxone +/- ampicillin OR vancomycin.
Ceftriaxone should not be used in younger infants because of the concern for ceftriaxone’s displacement of bilirubin from albumin and increase risk for indirect hyperbilirubinemia.

25. Treatment for febrile neutropenia
Broad-spectrum antibiotics with Pseudomonas coverage
Ex: use ceftazidime or piperacillin-tazobactam
Consider double coverage for possible resistant Pseudomonas
Ex: add amikacin or tobramycin
Consider gram-positive coverage (central line, skin infections)
Ex: add vancomycin
Consider anaerobic coverage (mucositis, typhlitis)
Ex: use piperacillin-tazobactam or add clindamycin
Teacher’s Guide:
There are several different regimens that may be used to treat febrile neutropenia.
In general, patients should be started on broad-spectrum antibiotics with gram negative (especially Pseudomonas) coverage such as ceftazidime or piperacillin-tazobactam .
For ill/septic patients, consider broadening antibiotics to include coverage for resistant GNR/Psudomonas such as adding amikacin or tobramycin.
If a patient is at high risk for Strep viridans infection (AML, relapsed leukemia patients) or if there is a concern for line infection, add gram positive coverage (ex vancomycin).
For concerns about typhlitis, incorporate anaerobic coverage by using piperacillin-tazobactam or by adding clindamycin.
These are general guidelines and empiric coverage should be discussed with the subspecialty fellow or attending.

26. Take home points
Infections are the most common cause of fever in children
During assessment of a child with fever, pay close attention to vital sign changes, overall appearance, and potential sites of infection
Closely monitor for clinical decompensation after antibiotic administration, particularly in patients at high-risk of developing sepsis

27. References
Baraff LJ. Management of fever without source in infants and children. Ann Emerg Med :
Meckler G, Lindemulder S. Fever and neutropenia in pediatric patients with cancer. Emerg Med Clin N Am :
Palazzi EL. Approach to the child with fever of unknown origin. UpToDate
Palazzi DL. Etiologies of fever of unknown origin. UpToDate
Tolan R. Fever of unknown origin: A diagnostic approach to this vexing problem. Clin Pediatr ;49: