Neutropenic Fever
www.idsociety.org
CID 2011; 52 (4):e56-e93
Learning Objectives
Definition and classification
– Identify appropriate patient
– Classify risk and type
Etiology / Microbiology
– Understand what you are evaluating for
– What “bugs” do you need to worry about
Clinical evaluation
Management
– Antibiotic selection, escalation, de-escalation
– Antibiotic duration
Definitions
Fever:
– Single oral temperature of ≥ 101°F (38.3°C)
– Temperature ≥ 100.4°F (38.0°C) over 1 hour
Neutropenia:
– ANC < 500 cells/mm3
– Expected ANC < 500 cells/mm3 within the
next 48 hours
Chemotherapy Induced
Neutropenia
Risk Stratification
High Risk
ANC ≤ 100 anticipated > 7 days
Hemodynamic instability
Oral or GI mucositis interfering with
swallowing or causing diarrhea
Neurologic/MS changes – new onset
Intravascular catheter infection
New pulmonary infiltrate, hypoxemia or
underlying chronic lung disease
Hepatic or renal insufficiency
MASCC < 21
Low Risk
Neutropenia anticipated ≤ 7 days
No active medical co-morbidity
Adequate hepatic and renal function
Multinational Assoc for Supportive
Care in Cancer Risk-Index Score
(MASCC) ≥ 21 of 26.
Burden of febrile neutropenia
No hypotension
No COPD
Solid or Heme w/o fungus
No IVF
Outpatient
Age < 60
0,3,5
5
4
4
3
3
2
Classification
Initial neutropenic fever
– Typically coincides with neutrophil nadir
– Standard protocol – concern for bacterial infection
Persistent neutropenic fever
– Fever despite 5 days of broad-spectrum antibacterials
– Complex management – concern for fungal infection
Recrudescent neutropenic fever
– Fever that recurs following initial response
– Wide differential
Etiology / Microbiology
Infectious
Bacterial translocation
– Intestinal
– Oropharyngeal
Community-acquired
– Respiratory viruses
Healthcare-associated
– MDR organisms
– C. diff
Opportunistic
– Herpes virus reactivation
– Fungal
Non-infectious
Underlying malignancy
Blood products
Tumor lysis
Hematoma
Thrombosis
Phlebitis
Atelectasis
Viscus obstruction
Drug fever
Myeloid reconstitution
Clinical Evaluation
Symptoms and signs of inflammation may be
minimal or absent in the severely neutropenic
patient
Cellulitis with minimal to no erythema
Pulmonary infection without discernable infiltrate on
radiograph
Meningitis without pleocytosis in the CSF
Urinary tract infection without pyuria
Peritonitis - abdominal pain without fever or guarding
Sickles, Arch Intern Med 1975; 135;715-9
The Work Up
Physical Exam:
Periodontium
Palate
Lung
Abdomen
Perineum
Skin
Tissue around the nails
BM biopsy site
Blood cultures x2
UA and Urine Cx
CXR
Targeted workup
–
–
–
–
C.diff
Exit site cultures
Catheter tip cultures
CT Abdomen/Pelvis
Ecthyma Gangrenosum
Bacteria:
Pseudomonas
GNR
Staphylococcus aureus
Fungus:
Aspergillus
Fusarium
Initial Neutropenic Fever
Empiric antibiotics:
– Pseudomonas and Streptococcus coverage
Cefepime OR Zosyn OR Imipenem
+/- Aminoglycoside
+/- Vancomycin
Coverage of bacteria
– Gram-negative organisms
Pseudomonas aeruginosa, E. coli, Klebsiella
– Gram-positive organisms (60%)
Coag neg Staph, Viridans Streptococcus, MRSA
Corynebacterium jeikeium
Empiric Vancomycin
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Blood Culture x2
Start Vanco/Cefepime/Amikacin
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Any Change in Management?
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Blood Culture x2
Start Vanco/Cefepime/Amikacin
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Blood Culture x2
HD 14 – Afebrile. Cx negative.
Continue Vanco/Cefepime/Amikacin
HD 14 – Cx E.coli (pan-S)
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Blood Culture x2
Start Vanco/Cefepime/Amikacin
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Blood Culture x2
HD 14 – Afebrile. Cx negative.
Continue Vanco/Cefepime/Amikacin
HD 14 – Afebrile. Cx E.coli (pan-S)
Cefepime
Cefazolin
Continue antibiotics until ANC > 500.
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Blood Culture x2
Start Vanco/Cefepime/Amikacin
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Blood Culture x2
Continue Vanco/Cefepime/Amikacin
HD 14 – Remains febrile. Clinically stable. Cultures negative.
Any Change in Management?
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Blood Culture x2
Start Vanco/Cefepime/Amikacin
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Blood Culture x2
Continue Vanco/Cefepime/Amikacin
HD 14 – Remains febrile. Clinically stable. Cultures negative.
Blood Culture x2
Continue Cefepime
HD 15 – Remains febrile. Clinically stable. Cultures negative.
Any Change in Management?
Early Management Summary
D/C vanco after 48 hours if no evidence of GP infection.
No need to perform more BC after first 48-72 hours if
patient clinically stable and no new symptoms.
Can simplify regimen if organism isolated. No need to
double cover Pseudomonas if sensitive to monotherapy.
Median time to defervescence ~5 days.
Treatment duration typically until ANC > 500.
If clinical worsening:
– Aggressive diagnostics
– Modify antibiotics to cover for resistant organisms
– Start anti-Candida therapy
Persistent Neutropenic Fever
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Vanco/Cefepime/Amikacin
HD 14 - Cefepime
HD 17 – Remains febrile. Clinically stable. Cultures negative.
Any Change in Management?
Persistent Neutropenic Fever
Up to 1/3 of patients with persistent neutropenic
fever after 7d Abx have invasive fungal infection.
Most common: Candida & Aspergillus
Look for a source:
CT Chest and Sinus
Fungal blood cultures
Galactomannan or b-D-Glucan
Biopsy suspicious skin lesions
Fungus 101
MOLD:
YEAST:
Candida, Cryptococcus
Aspergillus, Mucor
Invasive Mold
Aspergillus
Zygomyces
Mucor
Rhizopus
Absidia
Fusarium
Halo sign
Air crescent sign
Halo sign, air crescent sign, cavitating nodule  Invasive mold
Abnormal CT chest  BAL with biopsy or IR guided biopsy
Invasive Fungal Pneumonia
Anti-Fungal Therapy
Empiric:
–
–
–
–
Normal CT chest and/or sinus
Non-specific infiltrate on CT chest
No other evidence of invasive fungus
USE: Caspofungin or Amphotericin
Presumed or Definite Invasive Aspergillus:
–
–
–
–
Classic CT chest findings (no previous Voriconazole)
Positive culture or biopsy with typical hyphae
Positive Galactomannan
USE: Voriconazole
Persistent Fever
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.
Physical exam unremarkable. Vitals = SIRS. CXR negative.
Vanco/Cefepime/Amikacin
Cefepime
HD 17 – Remains febrile. Clinically stable. Cultures negative.
CT Chest & Sinus, Galactomannan
Continue Cefepime. Start anti-mold.
Consult ID
Invasive mold infection
No invasive mold infection
Voriconazole / Amphotericin
Echinocandin / Amphotericin
Case
65 M AML s/p induction chemotherapy
with daunorubicin and cytarabine.
Develops fever 12 days after completion of
induction chemotherapy. He notes some
non-specific abdominal pain and reports
diarrhea x2 days (C.diff negative x1).
Fever to 39OC, HR 110, BP 90/50.
Looks ill, diffuse mild abd tenderness
Next Steps
Blood Cx x2
UA and Urine Cx
PA/LAT CXR
Empiric Abx – Vanco/Cefepime/Amikacin
Results
Blood Cultures negative x 24 hours
UA and Urine Cx negative
CXR negative
C.diff EIA negative
He develops septic shock ~30 hours later
CT Abd/Pelvis
Blood Cultures x2 – anaerobic bottle: Clostridium septicum
Neutropenic Colitis
Typhlitis
– ANC < 500, usually AML
– Abdominal pain
– Diarrhea initially, ileus later
– CT or US with bowel wall thickening
– Rule-out C.diff
– Need anaerobic coverage:
Zosyn, Imipenem, Cefepime + Flagyl
Summary
Neutropenic fever – definition and classification
– High risk versus Low risk
– Initial, Persistent, Recrudescent
Etiology / Microbiology
– Bacterial translocation, CAI, HAI, opportunistic
Clinical evaluation
– Neutropenia = lack of inflammation
Management
–
–
–
–
Initial NF – need Pseudomonas and Strep coverage
De-escalate empiric therapy after 48-72 hours
Persistent/Recrudescent NF – think fungal infection
Duration until ANC > 500