Transcript FEBRILE NEUTROPENIA

Saima Abbas M.D
Infectious Diseases
Fellow-PGY5
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
( PMN,
Macrophages, NK
cells, Mast cells and
basophils)
 Complement
 Adaptive immunity
T cells CD 4 and CD 8
B cells

Case 1
July 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…..
OR
Am I missing febrile
Neutropenia???

If you are alert, you think…
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
A single oral temp  38.3  C
(101  F)
or

A temperature of  38  C
(100.4F) on two occasions
separated by 1 hour


You request her to repeat the
temperature and she reports 38. 2 C
(100.8 F)
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

ANC  500/mm3 or

 1000/mm3 and predicted
decline to  500/mm
~ Clin Inf Dis, 2002;34:730-51
ANC : Mr. Thomas

WBC 0.7

Segs = 38%

Bands = 2%
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)
Calculation
Neutropenia
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?
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

Risk of Infection as Absolute Neutrophil Count Declines
Epidemiology
 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
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 that
Carbapenicillin /Gentamicin decreased Mortality
by 33 %
~Journal of Infectious diseases, 1978;147:14
Epidemiology
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
Gram negative resurgence
1) More intensive
chemoTx
•Mucositis
2) In-dwelling catheters
• Cutaneous-IV portal
3) Selective antiBx
pressure
•Fluoroquinolones
• Co-trimoxazole
4) Antacids
•Promote orooesophageal
colonisation with
GPC
Duration of Neutropenia

< 7 days LOW risk

7 to 14 days INTERMEDIATE RISK

> 14 days HIGH RISK
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
Gram-positive cocci
and bacilli
 Staph. aureus
 Staphylococcus
epidermidis
 Enterococcus
faecalis/faecium
 Corynebacterium
species
Gram-negative
 bacilli and cocci
 Escherichia coli
 Klebsiella species
 Pseudomonas
aeruginosa
FUNGI
 Candida- Non
albicans emerging
 Aspergillus >> in
HSCT
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
Neisseria meningitidis
Hemophilus Influenzae

Splenectomy
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 –
 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

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
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
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
1. Neutropenia
  with severity of neutropenia (< 50/mm3)
  with duration of neutropenia (>7 days)
2.Bacteremia
 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
• 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
Model 2
(Klatersky et al MASCC 2000 J Clin Onc)
•No or Mild symptoms
•Moderate symptoms
•No Hypotension
•No COPD
•Solid tumour /
Haem malignancy
(no fungal infection)
•Outpatient
•No dehydration
•Age <60 yrs
LOW RISK=score>20
5
3
5
4
4
3
3
2
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
EMPIRIC ANTIMICROBIAL
THERAPY after Blood
Cultures.
Must be initiated within 1
hour
THREE approaches for IV
EMPIRIC therapy

IV MONO THERAPY

IV DUAL THERAPY
COMBINATION THERAPY
Mono or dual therapy + VANCOMYCIN

Monotherapy IV
1.
Extended spectrum Antipseudomonal
Cephalosporins
•
•
2.
Carbapenem
•
•
3.
Cefepime
Ceftazidime
Imipenem –Cilastatin
Meropenem
Anti –Pseudomonal PCN
•
•
Piperacillin- Tazobactam
Ticarcillin- Clavulanic acid
DUAL therapy
1.
an aminoglycoside
plus
an antipseudomonal penicillin
(with or without a beta-lactamase
inhibitor)
or
an extended-spectrum
antipseudomonal cephalosporin,
Dual therapy
(2) ciprofloxacin plus an
antipseudomonal penicillin.
Indications
 Unstable patient
 H/O P. aeruginosa colonization or
Invasive disease

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
4.
hypotension or other evidence of cardiovascular
impairment
5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole
vancomycin resistant
enterococcus

Linezolid

Daptomycin (avoid for pneumonia)

Quinopristin- Dalfopristin
PCN allergy
NON – ANAPHYLACTIC
If not allergic to cephalosporins
~ Cefepime
 ANAPHYLACTIC and allergic to
cephalosporins~Aztreonam +/- Aminoglycoside or a FQ

+/- Vancomycin if indicated
MAINTAIN BROAD
SPECTRUM ACTIVITY
FOR A MINIMUM OF 7
DAYS OR UNTIL ANC
>500
Antibiotic stopping guide
IDSA, 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…









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
Antifungals
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
 FLUCONAZOLE
 ITRACONAZOLE
 ECHINOCANDINS
 Voriconazole is NOT FDA approved for
empiric therapy for persistent fevers in
FN

Fluconazole ~ candida
Fluconazole
acceptable if NO
Moulds and Resistant
Candida
( C. Krusei and C.
glabrata )
Uncommon.

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.
Itraconazole
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




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

Antiviral drugs are not recommended for
routine use unless clinical or laboratory
evidence of viral infection is evident.

Granulocyte Transfusions
Granulocyte transfusions are not
recommended for routine use.
 Use
of Colony-Stimulating Factors
Use of colony-stimulating factors is
not routine but should be
considered in certain cases with
predicted worsening of course.
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
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.

Special Situations
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)

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
 Clostridium
Septicum
Clostridium Sordelli
Cover with PEN G ,AMP,
Clindamycin*
Broad Spectrum Abx ( carbapenem )
include Metronidazole if unsure of
Cdiff
* resistance of Clostridia to clindamycin
reported.
H/O leukemia and prolonged
antibiotic therapy
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
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?
 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




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

A
B
C
D
What will you do
next?
Stop Cefepime
Add G- CSF
Continue Cepepime
until ANC > 500 or
a minimum of 7
days.
Continue
Vancomycin for a
total of 7 days.
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)

Conclusions
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.
