L5: Febrile Neutropenia - Nav

What are neutrophils?

type of WBC and essential component of innate immune system that responds to invading pathogens:

• directly atk bact and fungi

• release cytokines to prod inflamm response at site of infection

How do you calculate absolute neutrophil count? (ANC)

(% segmented neutrophils + % bands) x WBC / 100

ANC < 1500 cells/microL

neutropenia

ANC < 500 cells/microL OR

ANC < 1000 cells/microL and predicted to decline to <500 cells over next 48hrs

severe neutropenia

ANC < 100 cells/microL + prolonged

profound neutropenia

(+ prolonged = high infection risk + fungal)

What is the association betw neutropenia and infection risk?

risk of infection inc w degree and duration of neutropenia

• risk highest in profound and prolonged neutropenia

  • prior to graft during hematopoietic cell transplant

  • after induction therapy for acute leukemia

febrile neutropenia (neutropenic fever)

severe neutropenia + single oral temp ≥ 101F (38.3C) or temp ≥100.4F (38C) sustained over 1 hour

• medical emergency

epidemiology

10-15% of pts with solid tumors

80% of pts w hematologic malignancies

25-30% of cases have complications: HoT, renal, respiratory, HF

11% mortality

important cause of healthcare resource consumption

What are the 3 risk factors for infection?

1. neutropenia: most important; effect of cytotoxic chemo on hematopoietic progenitor cells

2. mucosal barrier injury: effect of cytotxic chemo on epithelial cells (mouth and GI tract as mucositis); portal of entry for bact

3. dysbiosis: gut microbiota altered by chemo agents, total body irradiation, antimicrobial prophylaxis; pseudomonas aeru and yeast overgrowth

infectious etiology is iD in only 40-50% cases, most infections are caused by ___ what are the predominant pathogens? What are late causes of infection in severely immunocompromised hosts?

endogenous flora; gram positive and negative bacteria; fungi

MEMORIZE BACTERIA TABLE

antipseudomonal - beta lactam

what is the clinical presentation of febrile neutropenia?

fever: first and only sign of infection

• may be absent due to impaired inflam response

• considered a sign of infection until proven otherwise

types of infection

1. microbiologically documented infections

2. clinically docuemented infections

3. fever of unknown origin (FUO)

What should be done for dx and lab testing?

1. CBC w differential

2. chemistry tests (electrolytes, renal and hepatic function)

3. history and physical exam: classic signs of infection may be attenuated/absnet, common sites of infection should be assessed

4. two sets of blood cultures (b4 ABX)

5. chest radiograph

What are the risk stratification concepts?

1. pts receiving treatment for solid tumors are low risk (<7days)

2. pts receiving treatment for hematologic malignancies are high risk (≥ 7d)

Low risk febrile neutropenia has all of the following:

high risk has atleast one of the following

T/F MASCC and CISNE are scoring systems for risk assemssment

true

what is the site of care for high risk pts?

hospitalization and IV antimicrobials

what is the site of care for low risk patients?

outpatient setting w PO or IV antimicrobials if no logistical barriers; must have:

• residence in close prox to medical facility

• family member or caregiver at home

• access to a telephone and transportation

What are the principles of antibmicrobial therapy?

1. fever should be assumed to be due to infection until proven otherwise

2. pts should be assessed within 15 min after presenting for febrile neutropenia

3. first dose of empiric ABX should be admin within 60 min

4. empiric ABX should always cover pseudomonas aeru

What is empiric therapy in high risk patients?

1. monotherapy w IV antipseudomonal beta lactam

   1. pip/tazo

   2. cefepime (no good anaerobic cover)

   3. meropenem ± metronidazole (preferred if colonized w ESBL-producing enterobacterales)

   4. mipenem/cilastatin

What is not recommended for empiric therapy in high risk pts?

vancomycin; has increase risk of resistance and nephrotix

What are the indications for addition of vancomycin in high risk patients?

1. colonization w MRSA or penicillin resistant strep pneumo

2. skin and soft tissue infection

3. pneumonia

4. suspected IV catheter related infection

5. blood cultres positive for gram positive bact before final ID and susceptibilities

6. clinical instability (HoT, shock)

What is the empiric therapy in low risk pts?

1. first dose of IV antimicrobials admin in medical facility: similar to high risk antimicrobial choice

2. observed for ≥ 4 hrs before discharge

3. transitioned to PO fluoroquinolone-based regimen on discharge

PO fluoroquinolone based regimens

1. cipro + amox/clav (pref)

2. cipro + clindamycin

3. levoflox

4. moxiflox (doesn’t cover pseudomonas)

PO reigmens cant be used if pt received fluoroquinolone prophylaxis

What is the follow up therapy during febrile neutropenia for high risk pts?

1. vanco disc after 48 hrs if no resistant gram positive organisms

2. pts who become hemodynamically unstable should have their antimicrobial regimens broadened

3. empiric antifungal therapy (w activity against molds) considered for pts with persistent fever 4-7d

What is the follow up therapy during febrile neutropenia for low risk pts?

outpatients who do not defervesce after 48-72 hrs of ABX may need hospitalization

REVIEW DECISION TREE

In microbiologically or clinically documented infections, what is the duration of therapy?

continued until a standard course of therapy has been completed and ANC is ≥500 cells/microL

if fever of unknown origin, what is the duration of therapy? (controversial)

1. treatment continued until afebrile for ≥2d and ANC is ≥500 cells/microL and increasing OR

2. treatment d/c after ≥3d of IV ABX and afebrile for ≥2d irrespective of ANC (± transition to fluoroquinolone prophylaxis)

take home messages