Febrile neutropenia, Oncology, Paediatric oncology, Haematology, Infectious diseases

1. Febrile Neutropenia
Dr Arun George

2. Definition of Fever in Febrile
Neutropnenia
• A single oral temp  38.3  C
(101  F)
or
• An oral temperature of 38.0C (100.4F)
sustained for 1 h or that occurs twice within a
24-h period.
ESMO Guidelines Committee: October 2008, last update August 2016

3. Neutropenia
• Absolute neutrophil count (ANC) of
<0.5 × 10 9/l, or expected to fall below
0.5 × 10 9/l
ESMO Guidelines Committee: October 2008, last update August
2016

4. History and Physical Examination
• Lack of neutrophils  loss of inflammatory
response  limiting the ability to localize sites
of infection  fever as the only manifestation
of infection.
• Absence of physical signs and symptoms does
not reliably exclude the presence of infection
 need for empirical antibiotics.

5. Initial evaluation
Ensure Hemodynamic Stability and No NEW ORGAN
DYSFUNCTION
• History
– Underlying disease, remission and transplant status- spleen +/-
– Chemotherapy
– Drug history (steroids, any previous antibiotics)
– Allergies
• Focused Review of systems
• Transfusions
– Can cause fevers
• Lines or in-dwelling hardware

6. Examination
• Mouth, oropharynx, periodontium
• Lungs
• Abdomen for tenderness- RLQ (signs of Typhilitis)
• Perineum including the anus
• Skin and nail beds
• Intravascular catheter insertion sites
(75% of children with fever and neutropenia were
ultimately found to have a documented site of
infection.)

7. Laboratory Evaluation
• Complete blood cell count
• Serum creatinine
• Blood urea nitrogen
• Serum transaminases
• Blood culture

8. Other microbiologic studies
• Done if there are associated clinical symptoms.
• Nasal aspirate for viruses - if upper respiratory
fndings
• Stool for rotavirus in the winter months and for C.
difcile toxin in patients with diarrhea.
• Urinalysis and culture in young children or in
older patients with symptoms of urgency,
frequency, dysuria, or hematuria.
• Biopsy and culture of cutaneous lesions.

9. Radiology
• Chest radiographs - lower respiratory tract
symptoms
• Sinus flms - children >2 yr of age if rhinorrhea is
prolonged.
• Abdominal CT scans - profound neutropenia and
abdominal pain to evaluate for the presence of
typhlitis.

10. • Chest CT scan and galactomannan testing -
not responding to broad-spectrum antibiotics
who have continued fever and neutropenia for
longer than 96 hr.

11. Organisms
• Gram-positive cocci are the most common
pathogens identifed.
• Gram-negative organisms- P. aeruginosa, E.
coli, and Klebsiella
• Other multidrug-resistant Enterobacteriaceae
• Coagulase-negative staphylococci
• Viridans streptococci- oral mucositis

12. • Prolonged neutropenia- increased risk for
opportunistic fungal infections - with Candida
spp. and Aspergillus spp. being the most
commonly identifed fungi.
• Other fungi- Mucor spp., Fusarium spp., and
dematiaceous molds.

14. Recommendations

22. Monotherapy
Fourth-generation antipseudomonal β-lactam
cephalosporin; cefepime 150 mg/kg/day IV divided
q8h (max 2 g/day).
Carbapenem
Imipenem/cilastatin 60100 mg/kg/day (imipenem
component) IV divided q6h (max 4 g/day).
Meropenem 60 mg/kg/day IV divided q8h (max 3
g/day) (can be increased to 120 mg/kg/day IV
divided q8h with max 6 g/day in severe infection).

23. • Piperacillin/tazobactam (Zosyn) 240-300
mg/kg/day (piperacillin component) IV divided
q8h (max 16 g/day).
• Dual therapy (antipseudomonal β-lactam plus
an aminoglycoside)- Ceftazidime 150
mg/kg/day IV divided q8h (max 6 g/day) plus
tobramycin 7.5 mg/kg/day IV divided q8h.

24. Dual therapy can be considered in the
following clinical scenarios:
• Patient instability (e.g., hypotension, altered mental status,
oliguria, moderate to severe respiratory distress).
• Concern for resistant pathogens (e.g., extended-spectrum β-
lactamase (ESBL)-producing Serratia, Pseudomonas,
Acinetobacter, Citrobacter, Enterobacter, Klebsiella spp.).
• Need for synergism for specific pathogens (e.g.,
Enterococcus, Mycobacterium spp., MRSA).
• Need for synergism with specific infections (e.g.,
endocarditis, cryptococcal meningitis).

25. Vancomycin should be considered in the following
situations at a dose of 60 mg/kg/day IV divided q8h (max
4 g/day):
• Patients with AML receiving high-dose cytarabine due to
risk for S. viridians infection with associated septic shock
and acute respiratory distress syndrome.
• Presentation with hypotension or other evidence of
shock.
• Mucositis.
• Prior history of alpha-hemolytic Streptococcus infection.
• Skin breakdown or catheter site infection.
• Colonization with resistant organisms treated only with
vancomycin.
• Vegetations on echocardiogram.
• Severe pneumonia.

26. • Anaerobic drugs including clindamycin at a dose of 40
mg/kg/day IV (max 2.7 g/day) divided q68h,
metronidazole 30 mg/kg/day IV divided q8h (max 1.5
g/day), or oral vancomycin 40 mg/kg/day orally divided
q68h should be considered in the following situations:
• Typhlitis (neutropenic colitis).
• Significant mucosal breakdown.
• Perianal skin breakdown.
• Peritoneal signs or other abdominal pathology.
• C. difficile infection.

27. ONGOING MANAGEMENT OF FN
EXCLUDING EMPIRICAL THERAPY

29. Ongoing Management of Febrile
Neutropenia

31. Invasive fungal disease

35. Invasive fungal infections
• Invasive aspergillosis – Voriconazole,
Posaconazole, Micafungin, Caspofungin
• Mucormycosis- Liposomal amphotericin B
5 mg/kg/dose IV q24h.
• Invasive candidiasis- Treatment based on
sensitivities, often sensitive to fluconazole,
Echinocandins have been found to be at least non-
inferior to fluconazole.

36. G-CSF
• The use of hematopoietic growth factors shortens the
duration of
neutropenia but has not been proved to reduce
morbidity or mortality.
• Accordingly, the 2010 recommendations from the
Infectious Diseases Society of America do not endorse
the routine use of hematopoietic growth factors in
patients with established fever and neutropenia,
although the recommendations do note that
hematopoietic growth factors can be considered as
prophylaxis in those with neutropenia who
have a high risk for fever.

39. References
• 1. Nelson’s Textbook of Paediatrics
• 2. Lanzowsky
• 3.