Neutropenic Fever

Neutropenic Fever

www.idsociety.orgCID 2011; 52 (4):e56-e93

Learning ObjectivesDefinition 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 daysHemodynamic instabilityOral or GI mucositis interfering with swallowing or causing diarrheaNeurologic/MS changes – new onsetIntravascular catheter infectionNew pulmonary infiltrate, hypoxemia or underlying chronic lung diseaseHepatic or renal insufficiencyMASCC < 21

Low Risk

Neutropenia anticipated ≤ 7 daysNo active medical co-morbidityAdequate hepatic and renal functionMultinational Assoc for Supportive Care in Cancer Risk-Index Score (MASCC) ≥ 21 of 26.

Burden of febrile neutropenia 0,3,5No hypotension 5No COPD 4Solid or Heme w/o fungus 4No IVF 3Outpatient 3Age < 60 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

InfectiousBacterial translocation– Intestinal– Oropharyngeal

Community-acquired– Respiratory viruses

Healthcare-associated– MDR organisms– C. diff

Opportunistic– Herpes virus reactivation– Fungal

Non-infectiousUnderlying malignancyBlood productsTumor lysisHematomaThrombosisPhlebitisAtelectasisViscus obstructionDrug feverMyeloid reconstitution

Clinical EvaluationSymptoms and signs of inflammation may be minimal or absent in the severely neutropenic patient

Cellulitis with minimal to no erythemaPulmonary infection without discernable infiltrate on radiographMeningitis without pleocytosis in the CSFUrinary tract infection without pyuriaPeritonitis - abdominal pain without fever or guarding

Sickles, Arch Intern Med 1975; 135;715-9

The Work Up

Physical Exam:PeriodontiumPalateLungAbdomenPerineumSkinTissue around the nailsBM biopsy site

Blood cultures x2UA and Urine CxCXRTargeted workup– C.diff– Exit site cultures– Catheter tip cultures – CT Abdomen/Pelvis

Ecthyma Gangrenosum

Bacteria:PseudomonasGNRStaphylococcus aureus

Fungus:AspergillusFusarium

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 Algorithm65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 13 – Remains febrile. Clinically stable. Cultures negative.

Start Vanco/Cefepime/Amikacin Blood Culture x2

Any Change in Management?

Management Algorithm65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 13 – Remains febrile. Clinically stable. Cultures negative.

Start Vanco/Cefepime/Amikacin Blood Culture x2

Blood Culture x2 Continue Vanco/Cefepime/Amikacin

HD 14 – Afebrile. Cx negative. HD 14 – Cx E.coli (pan-S)

Management Algorithm65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 13 – Remains febrile. Clinically stable. Cultures negative.

Start Vanco/Cefepime/Amikacin Blood Culture x2

Blood Culture x2 Continue Vanco/Cefepime/Amikacin

HD 14 – Afebrile. Cx negative. HD 14 – Afebrile. Cx E.coli (pan-S)

Cefepime Cefazolin

Continue antibiotics until ANC > 500.

Management Algorithm65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 13 – Remains febrile. Clinically stable. Cultures negative.

Start Vanco/Cefepime/Amikacin Blood Culture x2

Blood Culture x2 Continue Vanco/Cefepime/Amikacin

HD 14 – Remains febrile. Clinically stable. Cultures negative.

Any Change in Management?

Management Algorithm65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 13 – Remains febrile. Clinically stable. Cultures negative.

Start Vanco/Cefepime/Amikacin Blood Culture x2

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 SummaryD/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 Fever65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 17 – Remains febrile. Clinically stable. Cultures negative.

Vanco/Cefepime/Amikacin

HD 14 - Cefepime

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 & AspergillusLook for a source:CT Chest and SinusFungal blood culturesGalactomannan or b-D-GlucanBiopsy suspicious skin lesions

Fungus 101

YEAST:

Candida, Cryptococcus

MOLD:

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 TherapyEmpiric:– 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 Fever65 AML s/p induction chemotherapy – HD 12 neutropenic fever.

Physical exam unremarkable. Vitals = SIRS. CXR negative.

HD 17 – Remains febrile. Clinically stable. Cultures negative.

Vanco/Cefepime/Amikacin

Cefepime

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 x2UA and Urine CxPA/LAT CXREmpiric Abx – Vanco/Cefepime/Amikacin

Results

Blood Cultures negative x 24 hoursUA and Urine Cx negativeCXR negativeC.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

SummaryNeutropenic 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