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Saima Abbas M.D Infectious Diseases Fellow-PGY5. FEBRILE NEUTROPENIA. Why is this an Oncologic emergency ??. Infection + ABX + Immune system = cure. Normal Gross Anatomy Skin Integrity Intact mucous membranes Intact ciliary function Absence of Foreign Bodies. Innate Immunity

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saima abbas m d infectious diseases fellow pgy5
Saima Abbas M.D

Infectious Diseases



infection abx immune system cure
Infection + ABX + Immune system = cure
  • Normal Gross Anatomy
  • Skin Integrity
  • Intact mucous membranes
  • Intact ciliary function
  • Absence of Foreign Bodies
  • Innate Immunity

( PMN,

Macrophages, NK cells, Mast cells and basophils)

  • Complement
  • Adaptive immunity

T cells CD 4 and CD 8

B cells

case 1 july 10 th 2009 nf 1
Case 1July 10th 2009 - NF 1

You are paged at 5:00am by the nurse taking care of Mr. Thomas on 4 AB

He spiked a fever of 38 C (100.4F) one hour ago.

-There is no order for Tylenol.


~ You check your Hem Oncology List .

Per sign out:

The patient was recently diagnosed with AML is S/P chemotherapy and is stable.

  • You can
    • Order Tylenol and take the next page.
        • OR…..

Am I missing febrile Neutropenia???

  • If you are alert, you think…
what are the facts you need to know
What are the facts you need to know?
  • Does 38  C define febrile neutropenia?
  • What’s his Absolute Neutrophil Count?
  • Any transfusion in the last 6 hours?
definition of fever in fn
Definition of Fever in FN
  • A single oral temp  38.3  C

(101  F)


  • A temperature of  38  C

(100.4F) on two occasions separated by 1 hour

don t be tricked
Don’t be tricked
  • If temperature 37  38 C , repeat temperature in 1 hour to see if the above criteria for treatment are met
  • Clinical signs of septicemia
  • Good history of fever detected by patient before admission and afebrile when you evaluate the patient.
definition of neutropenia
Definition of Neutropenia
  • ANC  500/mm3 or
  • 1000/mm3 and predicted

decline to  500/mm

~ Clin Inf Dis, 2002;34:730-51

anc mr thomas
ANC : Mr. Thomas
  • WBC 0.7
  • Segs = 38%
  • Bands = 2%
absolute neutrophil count
Absolute Neutrophil Count

(Total # of WBC) x (% of Neutrophils) = ANC

  • Take the percent of neutrophils (may also be polys or segs) + percent bands
  • Convert percent to a decimal by dividing by 100 (Example 40% = 40/100 = 0.40) (*move the decimal 2 points to the left)
  • Multiply this number by the total White Blood Cells (WBC)
  • Normal ANC 1500 to 8000 cells/mm³
  • Neutropenia: ANC < 1500 cells / mm3
  • Mild Neutropenia: 1000-1500 cells / mm3
  • Moderate Neutropenia: 500-999 cells / mm3
  • Severe Neutropenia: < 500 cells / mm3
  • Profound Neutropenia: <100 cells/ mm³
when does neutropenia occur
When Does Neutropenia Occur?
  • Most chemotherapy agents/protocols cause neutropenia nadir at 10-14 days
  • But can see anytime from a few days after chemotherapy to up to 4-6 weeks later depending on the agents used
  • Up to 60% febrile neutropenia episodes = infection (microbiological or clinical)
  • ~20% patients with ANC <100 cells/mm³ with febrile neutropenia episodes have bacteremias.
epidemiology nejm 1971 284 1061
Epidemiology --NEJM, 1971;284:1061

Retrospective data have shown that

  • ~ 50 % of Pseudomonas Aeruginosa Bacteremia result in death within 72 hours when ANC is < 1000
  • Early trials aimed at Pseudomonas showed thatCarbapenicillin /Gentamicin decreased Mortality by 33 %

~Journal of Infectious diseases, 1978;147:14


Viscoli et al, Clin Inf Dis;40:S240-5

  • Changing etiology of bacteremia

IATG-EORTC 1973-2000 trials of febrile neutropenia

  • Gram positive dominant since mid 1980s
  • 1) More intensive chemoTx
    • Mucositis
  • 2) In-dwelling catheters
    • Cutaneous-IV portal
  • 3) Selective antiBx pressure
    • Fluoroquinolones
    • Co-trimoxazole
  • 4) Antacids
    • Promote oro-oesophageal colonisation with GPC

Gram negative resurgence

duration of neutropenia
Duration of Neutropenia
  • < 7 days LOW risk
  • 7 to 14 days INTERMEDIATE RISK
  • > 14 days HIGH RISK
duration of neutropenia 1988 rubin and colleagues
Duration Of Neutropenia 1988,Rubin and colleagues
  • < 7 days of neutropenia

~ response rates to initial antimicrobial therapy was 95%, compared to only 32% in patients with more than 14 days of neutropenia ( <.001)

~ patients with intermediate durations of neutropenia between 7 and

14 days had response rates of 79%

common microbes
Common Microbes

Gram-positive cocci and bacilli

  • Staph. aureus
  • Staphylococcus epidermidis
  • Enterococcus faecalis/faecium
  • Corynebacterium species


  • bacilli and cocci
  • Escherichia coli
  • Klebsiella species
  • Pseudomonas aeruginosa


  • Candida- Non albicans emerging
  • Aspergillus >> in HSCT
initial evaluation
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

THINK Strep. Pneumoniae



  • Splenectomy
exam be prepared to find no signs of inflammation
Exam (be prepared to find no signs of inflammation)
  • HEENT Look in the mouth any oral sores – periodontium, the pharynx
  • Lungs
  • Abdomen for tenderness- RLQ (signs of Typhilitis)
  • Perineum including the anus -No rectal exam !
skin exam ask the patient for any area of tenderness
Skin Exam- Ask the patient for any area of tenderness?

Skin –

  • Bone marrow aspirations sites,
  • vascular catheter access sites
  • and tissue around the nails
  • Rashes (Drug eruptions/herpes zoster reactivation / Petechial rashes all are common in these patients)
febrile neutropenia investigation
Febrile neutropeniaInvestigation
  • Complete Blood Count (with Differential)

-White cells, haemoglobin, platelets

  • Biochemistry

-Electrolytes, urea, creatinine, Liver function

  • Microbiology

-Blood cultures (peripheral and all central line lumens)

-Oral ulcers or sores –send swabs ( Viral Cx and fungal Cx )

-Exit site swabs

-Wound swabs

-Urine Cultures (SSx/Foley Catheter) [- pyuria ?? UA]

-Stool Cultures and CDiff Toxin/PCR

  • Radiology

-Chest Xray +/- CT abdomen/pelvis

lumbar puncture
Lumbar puncture-
  • Examination of CSF specimens is not recommended as a routine procedure but should be considered if a CNS

infection is suspected and thrombocytopenia is absent or manageable.

skin lesions
Skin lesions
  • Aspiration or biopsy of skin lesions suspected of being infected should be
  • performed for cytologic testing, Gram staining, and culture
imaging in fn
  • CXR if Symptomatic or if out pt Rx considered
  • High resolution CT Chest Indicated ONLY if persistent fevers with pulmonary symptoms after initiation of empiric Abx
  • CTA if suspect PE
  • CT abdomen for Necrotizing Enterocolitis or Typhilitis
  • CT brain R/o ICH / MRI of the spine or brain - more for evaluation of metastatic disease than FN
stratify risk of complications
Stratify risk of complications

1. Neutropenia

  •  with severity of neutropenia (< 50/mm3)
  •  with duration of neutropenia (>7 days)


  • Gram negative > gram positive

3.Underlying malignancy and status

  • Acute Leukemia
  • Relapsed disease
  • Solid malignancies: Local effects eg obstruction, invasion

4.Co-morbidities, age >60

high risk patients
HIGH risk Patients
  • • Prolonged Neutropenia (>14 days)
  • Haematological malignancy/ Allogenic HSCT
  • • Myelosuppresive chemotherapy
  • • Concurrent chemotherapy and radiotherapy
  • • Age >60
  • • Co-morbidities eg. Diabetes, poor nutritional status.
  • • Bone marrow involvement of cancer
  • • Delayed surgical healing or open wounds
  • • Significant mucositis
  • • Unstable (eg hypotensive, oliguric)
  • • On steroid dose >20mg prednisone daily
  • • Recent hospitalization for infection

a Concomitant condition of significance (e.g.,shock, hypoxia, pneumonia,

or other deep organ infection, vomiting, or diarrhea).

risk model
Risk model
  • Model 2
  • (Klatersky et al MASCC 2000 J Clin Onc)
  • No or Mild symptoms 5
  • Moderate symptoms 3
  • No Hypotension 5
  • No COPD 4
  • Solid tumour / 4
  • Haem malignancy
  • (no fungal infection)
  • Outpatient 3
  • No dehydration 3
  • Age <60 yrs 2
  • LOW RISK=score>20
oral vs iv
  • For patients who are low risk for developing infection-related complications during the course of neutropenia,

~ Oral ciprofloxacin plus amoxicillin/clavulanate

~ Oral ciprofloxacin plus clindamycin

for PCN allergy

if inpatient and high risk
If inpatient and high risk
  • EMPIRIC ANTIMICROBIAL THERAPY after Blood Cultures.Must be initiated within 1 hour
three approaches for iv empiric therapy
THREE approaches for IV EMPIRIC therapy

Mono or dual therapy + VANCOMYCIN


Monotherapy IV

  • Extended spectrum Antipseudomonal Cephalosporins
      • Cefepime
      • Ceftazidime
  • Carbapenem
      • Imipenem –Cilastatin
      • Meropenem
  • Anti –Pseudomonal PCN
      • Piperacillin- Tazobactam
      • Ticarcillin- Clavulanic acid
dual therapy
DUAL therapy

1. an aminoglycoside


an antipseudomonal penicillin

(with or without a beta-lactamase inhibitor)


an extended-spectrum

antipseudomonal cephalosporin,

dual therapy42
Dual therapy

(2) ciprofloxacin plus an

antipseudomonal penicillin.

  • Indications
  • Unstable patient
  • H/O P. aeruginosa colonization or Invasive disease
5 indications for vancomycin
5 Indications for Vancomycin

1. clinically suspected serious catheter-related infections

2. known colonization with penicillin- and

cephalosporin-resistant pneumococci or MRSA,

3. positive results of blood culture for gram-positive

  • hypotension or other evidence of cardiovascular impairment

5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole

vancomycin resistant enterococcus
vancomycin resistant enterococcus
  • Linezolid
  • Daptomycin (avoid for pneumonia)
  • Quinopristin- Dalfopristin
pcn allergy
PCN allergy

If not allergic to cephalosporins

~ Cefepime

  • ANAPHYLACTIC and allergic to cephalosporins-

~Aztreonam +/- Aminoglycoside or a FQ

+/- Vancomycin if indicated

antibiotic stopping guide idsa clin infect disease 2002
Antibiotic stopping guideIDSA, Clin Infect Disease, 2002
  • Minimum 1 week of therapy if
    • Afebrile by day 3
    • Neutrophils >500/mm3 (2 consecutive days)
    • Cultures negative
    • Low risk patient, uncomplicated course
  • > 1 week of therapy based if
    • Temps slow to settle (>3 days)
    • Continue for 4-5 days after neutrophil recovery (>500/mm3 )
  • Minimum 2 weeks
    • Bacteraemia, deep tissue infection
    • After 2 weeks if remains neutropenic (< 500/mm3), BUT afebrile, no disease focus, mucous membranes, skin intact, no catheter site infection, no invasive procedures or ablative therapy planned…cease antibiotics and observe
when temperatures do not go away
When temperatures do not go away…
  • Non-bacterial infection (eg fungal, viral)
  • Bacterial resistance to first line therapy (MRSA, VRE)
  • Slow response to drug in use
  • Superinfection
  • Inadequate dose
  • Drug fever
  • Cell wall deficient bacteria (eg Mycoplasma, Chlamydia)
  • Infection at an avascular site (abscess or catheter)
  • Disease-related fever
  • Easy to Initiate/ Difficult to stop
  • Aggressive search for Fungal Infections
  • Pulmonary Aspergillosis/Sinusitis / Hepatic Candidiasis
  • CT Chest and Abdomen
  • CT Sinuses
  • Cultures of suspicious skin lesions
anti fungals
  • AMPHO B IV drug of choice for high risk patients

Alternative options

  • Voriconazole is NOT FDA approved for empiric therapy for persistent fevers in FN
fluconazole candida
Fluconazole ~ candida
  • Fluconazole acceptable if NO

Moulds and Resistant Candida

( C. Krusei and C. glabrata )


Low risk patients

  • DO NOT Use Fluconazole if
  • Evidence of Sinusitis or
  • Radiographic evidence of Evidence of Pulmonary disease
  • If patient has received Fluconazole prophylaxis before.
  • In a recent controlled study of 384 neutropenic patients with cancer, itraconazole and amphotericin B were equivalent in efficacy as empirical antifungal therapy.

FOR BOARDS use AmphoB OR Itraconazole- hopefully should not ask you to choose between Itraconazole and Ampho B

antibiotic prophylaxis for afebrile neutropenic patients
Antibiotic Prophylaxis for Afebrile Neutropenic Patients
  • Use of antibiotic prophylaxis is not routine because of emerging antibiotic resistance **, except for
  • Trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonitis.
  • Antifungal prophylaxis with fluconazole
  • Antiviral prophylaxis with acyclovir or ganciclovir are warranted for patients undergoing allogenic hematopoietic stem cell transplantation.

** CID 40:1087&1094,2005

NEJM 353:977,988&1052,2005

use of antiviral drugs
Use of Antiviral Drugs
  • Antiviral drugs are not recommended for routine use unless clinical or laboratory evidence of viral infection is evident.

Granulocyte TransfusionsGranulocyte transfusions are not recommended for routine use.

  • Use of Colony-Stimulating FactorsUse of colony-stimulating factors is not routine but should beconsidered in certain cases with predicted worsening of course.
role of g csf
Role of G-CSF
  • Studies of G-CSF used in febrile neutropenia show:
    •  Length of neutropenia but generally not hospitalization
    • No mortality advantage
  • Generally not recommended
    • Exception may be those in high risk group esp. if unstable
updates not for boards but for clinical practice
Updates not for BOARDS but for clinical practice
  • JAC 57:176,2006
  • A meta analysis of 33 RCTs until Feb 2005 on Antipseudomonal B lactams as MONOtherapies showed that ~CEFEPIME increases 30 day all cause mortality

~ Carbapenems were associated with increased Pseudomembranous colitis.

neutropenic enterocolitis or typhilitis
Neutropenic Enterocolitis or Typhilitis
  • Inflammatory process involving colon and/or small bowel
  • ischemia, necrosis, bacteremia
  • ( translocation from gut) hemorrhage, and perforation.
  • Fever and abdominal pain ( typically RLQ).
  • Bowel wall thickening on ultrasonography or CT imaging.
treatment 50 70 mortality
Treatment ( 50-70% mortality)
  • Initial conservative management
      • bowel rest,
      • intravenous fluids,
      • TPN,
      • broad-spectrum antibiotics
      • and normalization of neutrophil counts.
  • Surgical intervention
      • obstruction, perforation, persistent gastrointestinal bleeding despite correction of thrombocytopenia and coagulopathy, and clinical deterioration.
consider pseudomonal and clostridial coverage in empiric therapy
Consider Pseudomonal and Clostridial coverage in Empiric therapy
  • Clostridium SepticumClostridium SordelliCover with PEN G ,AMP, Clindamycin*Broad Spectrum Abx ( carbapenem )include Metronidazole if unsure of Cdiff * resistance of Clostridia to clindamycin reported.
angioinvasive aspergillosis
Angioinvasive Aspergillosis
  • Confirm with Biopsy
  • Aggressive Antifungal Therapy
    • Voriconazole (Drug of Choice)
    • Caspofungin FDA approved for Ampho and Voriconazole refractory Aspergillus.
case 1 mr thomas
Case 1- Mr. Thomas
  • June 20th 2009 – diagnosed AML
  • June 21st 2009 – R subclavian

Hickman placed and Chemotherapy initiated

  • Remission Induction S/P 7+ 3 regimen Cytarabine (Ara C) and Daunorubicin
  • June 28th 2009 - last dose of chemotherapy.
  • July 10th 2009 - Febrile Neutropenia
  • ANC 280 ANC < 500 last 2 days

Experiences chills with CVC flushing and erythema and tenderness is noted over the hickman exit site.

  • Allergies NKDA
  • Labs Pancytopenic
  • LFTS ok Creatinine 1.0
what is the best next step
What is the best next step?
  • 1- Cefepime or Zosyn IV stat
  • 2- Vancomycin IV stat
  • 3- CXR
  • 4- Blood cultures-central and peripheral
  • 5- Fluconazole IV stat
cefepime and vancomycin are initiated
Cefepime and Vancomycin are initiated
  • Blood cultures are + for MRSE 2/2.
  • Pt becomes afebrile day 4 of ABX.
  • Surveillance Blood cultures are Negative. Patient is stable.
  • ANC = 300 by DAY 4
  • What will you do next?

A Stop Cefepime

B Add G- CSF

C Continue Cepepime until ANC > 500 or a minimum of 7 days.

D Continue Vancomycin for a total of 7 days.

remember for boards
Remember for boards
  • Do not order CT scan in a neutropenic patient with a normal CXR.
  • In clinical practice if patient remains febrile for 3 to 5 days then the next step is HRCT. ( 50 % of patients with + imaging have a normal CXR)
  • Febrile Neutropenia is a serious complication of chemotherapy
  • Be vigilant for febrile neutropenia in chemotherapy patients
  • Be vigilant for infection even when no fever
  • Initiate EMPIRIC antibiotics immediately.
  • Several treatment options depending on risk stratification.