1) Febrile neutropenia is a potentially life-threatening complication in cancer patients undergoing chemotherapy, as fever may be the first sign of infection during periods of low white blood cell and neutrophil counts. 2) Prompt evaluation and initiation of broad-spectrum antibiotics within 60 minutes is critical, as infection is a major cause of mortality. Initial recommended antibiotics include cefepime, ceftazidime, or meropenem. 3) Patients are classified as high or low risk based on severity and expected duration of neutropenia, with high risk patients requiring more intensive treatment and monitoring for complications like invasive fungal infections.

1. FEBRILE
NEUTROPENIA
Dr. Saba Fatima

2. ■ Infection is a major cause of morbidity and mortality in cancer patients
■ Fever may be the first manifestation of a life-threatening infection, particularly during periods of
neutropenia.
■ Febrile episodes occur in approximately one-third of neutropenic children with chemotherapy-induced
neutropenia or after hematopoietic cell transplantation
■ The demonstration of markedly reduced infection-related morbidity and mortality with the empiric use
of broad-spectrum antibiotics during periods of febrile neutropenia was a major advance in the field of
oncology in the 1970s

3. ■ Neutropenia:
“Neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/microL”
■ OR
“as an ANC <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL during the next 48 hours”
The degree of neutropenia is classified as follows:
Mild – ANC 1000 to 1500/microL
Moderate – ANC 500 to 1000/microL
Severe – ANC <500/microL.
An increased risk becomes apparent at an ANC <1000 cells/microL, is greater at an ANC ≤500 cells/microL and
greatest at an ANC ≤100 cells/microL (profound neutropenia).
Patients with neutropenia projected to last for more than seven days also are at a higher risk of infection than are
those with neutropenia of shorter duration

4. ■ ANC = total white blood cell count (cells/microL)
x (percent neutrophils + percent bands) ÷ 100

5. ■ Fever generally is defined
“as a single oral temperature ≥38.3°C (101°F) in neutropenic patients”
OR
“A temperature ≥38°C (100.4°F) for longer than one hour or two elevations >38°C (100.4°F) during a 12-
hour period”

6. RISK CATEGORY :
■ High-risk patients
■ have an increased risk of severe infection.
■ Neutropenia (ANC <500 cells/microL) anticipated to last >7 days
■ Infectious DiseasesSociety of America guidelines, patients with an absolute neutrophil count ≤100
cells/microL for >7 days are considered to be at high risk for serious complications.
■ hepatic insufficiency (aminotransferase levels >5 times normal values) or renal insufficiency
(creatinine clearance <30 mL/min)
■ Comorbid medical problems
■ Patients with infant acute lymphoblastic leukaemia, acute myeloid leukaemia, or within 30 days of
hematopoietic cell transplant

7. ■ LOW RISK :
■ Neutropenia expected to resolve within seven days
■ Stable and adequate hepatic and renal function
■ No active comorbidities

8. ETIOLOGY OF FEVER
■ What can be possible causes for fever in pediatric oncology patients ???

9. ■ EVLAUATION :
■ Infection is a major cause of morbidity and mortality in cancer patients.
■ Serious infection may occur in the absence of fever and/or neutropenia and must be considered in the
paediatric cancer patient who is febrile and neutropenic, febrile but not neutropenic, or neutropenic
and afebrile with signs of infection or clinical deterioration
■ Prompt initiation of empiric therapy can be life-saving, so rapid (but thorough) evaluation is critical.

10. HISTROY :
■ New site-specific symptoms
■ Antimicrobial prophylaxis
■ Infection exposures
■ History of documented infections or colonization
■ Concomitant non-infectious cause of fever ( receipt of blood products)
■ Underlying comorbid conditions (eg, diabetes, recent surgery)
■ Previous chemotherapy, agents used, and the stage of therapy (to anticipate the
length of the neutropenic episode)
■ Intravascular catheters or other devices

11. ■ PHYSICAL EXAMINATION:
■ Abnormal vital signs -particularly tachycardia (even without hypotension)
■ Skin: especially folds, areas surrounding nail beds, central venous line exit sites and subcutaneous
tunnel, if present, and sites of bone marrow aspiration and lumbar puncture
■ Sinuses
■ Oropharynx ( with attention to the gingiva)
■ Lungs
■ Abdomen
■ Perineum (particularly the perianal and labial regions)
■ Mild erythema or tenderness should not be ignored because signs of inflammation in the neutropenic
patient may be subtle.
■ Repeated physical examinations are essential.
■ Visual signs of inflammation may become evident only when neutrophil counts are recovering.

12. WHAT LAB INVESTIGATIONSYOU WOULD LIKETO
DO ???

13. ■ The cornerstone of therapy for the febrile neutropenic patient is prompt initiation of empiric broad-
spectrum antibiotics.
■ Administration of antibiotic therapy more than 60 minutes after presentation has been associated
with increased adverse outcomes and length of stay.
■ In an observational study in paediatric cancer patients, receipt of antibiotics within 60 minutes of
presentation was associated with decreased rates of ICU consultation or admission among.
■ A prospective study in adult cancer patients also demonstrated increased 28-day mortality when
antibiotics were administered between 31 and 60 minutes after presentation than when they were
administered within 30 minutes (18 versus 3 percent)
■ Antibiotics must be administered within 30 minutes if there are signs of sepsis and within 60
minutes if there are no signs of sepsis.
■ All patients must be discussed with the on-call oncology consultant/fellow (or consultant
paediatrician in regional centres) after the 1st dose of intravenous antibiotic

14. ■ General guidelines have been published for the use of empiric antibiotics during episodes of fever
and neutropenia:
■ Infectious DiseasesSociety of America (IDSA), most recently updated in 2010,
■ The International Paediatric Fever and Neutropenia Guideline Panel (2017),
■ National Institute for Health and Care Excellence (NICE) (2012) .
■ The guidelines emphasize that, when choosing empiric therapy, each practitioner should consider :
■ Whether the child is at high or low risk of infection
■ Drug allergies of the patient, if any
■ Presence of organ dysfunction, particularly renal and hepatic
■ The particular chemotherapeutic regimen and when it was administered: for example, an association
exists between viridians streptococcal infection and high-dose cytarabine therapyWhether the patient
was receiving prophylactic antimicrobials
■ Previous colonization with resistant bacteria (eg, methicillin-resistant S. aureus [MRSA]; vancomycin-
resistant enterococcus; extended-spectrum beta-lactamase producing organism, including Klebsiella
pneumoniae carbapenemase)

15. ■ Initial therapy
■ uncomplicated episodes of fever in neutropenic patients:
■ Recommended agents include:
Cefepime – 50 mg/kg intravenously (IV) every 8 hours up to a maximum of 2 g per dose
Ceftazidime – 50 mg/kg IV every 8 hours up to a maximum of 2 g per dose
Meropenem – For children ≥3 months of age: 20 mg/kg IV every 8 hours up to a maximum of 1 g per
dose for non-central nervous system infections and 40 mg/kg IV every 8 hours up to a maximum of 2
g/dose for central nervous system infections
Piperacillin-tazobactam – For infants and children <30 kg: 100 mg/kg of piperacillin component IV every
6 to 8 hours
children ≥30 kg: 3 g of piperacillin component IV every 6 hours; the maximum daily dose of the
piperacillin component is 16 g/day

16. ■ Additional antimicrobials may be added to the initial regimen based on the:
■ clinical presentation
■ suspected antimicrobial resistance
■ management of complications ( if abdominal symptoms are present, particularly abdominal pain or
blood per rectum, metronidazole should be added if the initial combination does not adequately
cover anaerobic organismsOR if infection with MRSA is suspected, the addition of vancomycin may
be beneficial.)
■ vancomycin —Vancomycin is not routinely recommended in the initial empiric regimen for patients with
fever and neutropenia. It should be reserved for children with clear indications for additional gram-
positive coverage.

17. ■ The 2010 guidelines from the IDSA recommend that vancomycin be reserved for the following clinical
scenarios:
■ Hypotension or other signs of cardiopulmonary deterioration
■ Radiographically documented pneumonia
■ Clinically suspected central venous line site infection (eg, chills or rigors with infusion through the
catheter and cellulitis around the catheter entry or exit site)
■ Skin or soft tissue infection at any site
■ Known colonization with MRSA, penicillin- and cephalosporin-resistant Streptococcus pneumoniae
■ When a blood culture has been reported to be growing gram-positive bacteria and identification and
susceptibility testing are pending
■ Additional indications for vancomycin may include
■ Substantial mucositis
■ Prophylaxis with quinolones during afebrile neutropenia
■ Previous history of infection with penicillin-resistant streptococci
■ Recent intensive chemotherapy associated with a high risk for infection with organisms (eg, alpha-
hemolytic streptococcal infection following high-dose cytarabine)

18. ■ Initial oral therapy for low-risk patients — Although it has not been well-studied in children, the
combination of ciprofloxacin and amoxicillin-clavulanate is an option for combination therapy for
low-risk patients who are candidates for oral empiric therapy .

19. ■ Modifications of initial therapy :After initiation of the initial antimicrobial regimen, patients should be
monitored closely. Modification of the regimen may be warranted based upon a variety of clinical
scenarios
■ Change in clinical status or vital signs
■ Isolation of a blood-borne organism
■ Documented clinical or microbiologic infection
■ Development of signs or symptoms of a localized infection
■ Persistent fever for more than four days
■ Recurrent fever after initial defervescence

20. Antifungal therapy
■ Clinically occult fungal infection must be considered in children with persistent fever (ie, ≥4 days) and
neutropenia despite empiric antibacterial therapy .
■ Additional risks for invasive fungal infection include acute myeloid leukemia, relapsed acute leukemia,
high-risk acute lymphoblastic leukemia, prolonged neutropenia (>10 days), highly myelosuppressive
chemotherapy, high-dose glucocorticoids (usually defined as prednisone ≥20 mg per day, or >2 mg/kg
per day for patients weighing <10 kg) for ≥14 days and allogeneic hematopoietic cell transplant
recipients
■ The 2017 IPFNG suggest that galactomannan should not be used to guide initiation of empiric
antifungal therapy because of its poor positive predictive value and inability to exclude non-Aspergillus
molds. Although beta-D glucan is widely used in adult cancer patients, it is not recommended in
children because its diagnostic accuracy has not been demonstrated in this population

21. ■ Duration of therapy —The duration of empiric antibiotic therapy depends upon the clinical
circumstances of the individual patient.
■ The traditional endpoint has been negative blood cultures for at least 48 hours
■ resolution of fever for at least 24 hours
■ resolution of neutropenia (ie, absolute neutrophil count [ANC] >500 cells/microL)

22. ■ Outpatient management — Outpatient management of fever and neutropenia with
intravenous or oral antibiotics may be an option for carefully selected low-risk patients
if daily follow-up is ensured

26. REFERNCES
■ https://www.rch.org.au/clinicalguide/guideline_index/Fever_and_suspected_or_confir
med_neutropenia/#initial-assessment-and-management
■ Guideline for the Management of Fever and Neutropenia in ChildrenWith Cancer and
Hematopoietic Stem-CellTransplantation Recipients: 2017 Update
■ Fever and suspected or confirmed neutropenia-Clinical Practice Guidelines-
■ Up to date -Fever in children with chemotherapy-induced neutropenia