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7/29/2019 Febrile Neutropenia Final 7-29
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Saima Abbas M.DInfectious Diseases
Fellow-PGY5
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Why is this an Oncologic
emergency ??
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Infection + ABX + Immune
system = cure Normal Gross
Anatomy
Skin Integrity
Intact mucousmembranes
Intact ciliary
function
Absence of
Foreign Bodies
Innate Immunity
( PMN,
Macrophages, NK
cells, Mast cells andbasophils)
Complement
Adaptive immunity
T cells CD 4 and CD 8
B cells
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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 (100.4F) onehour ago.
-There is no order for Tylenol.
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~ 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..
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OR
If you are alert, you think
Am I missing febrile
Neutropenia???
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What are the facts you need to
know?
Does 38 C define febrile neutropenia?
Whats his Absolute Neutrophil Count?
Any transfusion in the last 6 hours?
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Definition of Fever in FN
A single oral temp 38.3 C(101 F)
or
A temperature of 38C(100.4F) on two occasions
separated by 1 hour
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You request her to repeat the
temperature and she reports 38. 2 C
(100.8 F)
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Dont be tricked
If temperature 3738C , repeattemperature in 1 hour to see if theabove criteria for treatment are met
Clinical signs of septicemia
Good history of fever detected by
patient before admission and afebrilewhen you evaluate the patient.
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Definition of Neutropenia
ANC 500/mm3 or
1000/mm3 and predicted
decline to 500/mm
~ Clin Inf Dis, 2002;34:730-51
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ANC : Mr. Thomas
WBC 0.7
Segs = 38%
Bands = 2%
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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 tothe left)
Multiply this number by the total White
Blood Cells (WBC)
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Calculation
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Neutropenia
Normal ANC 1500 to 8000 cells/mm
Neutropenia: ANC < 1500 cells / mm3
Mild Neutropenia: 1000-1500 cells / mm3
Moderate Neutropenia: 500-999 cells /
mm3
Severe Neutropenia: < 500 cells / mm3
Profound Neutropenia:
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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 4-6weeks later depending on the agents
used
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Risk of Infection as Absolute Neutrophil CountDeclines
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Epidemiology
Up to 60% febrile neutropeniaepisodes = infection(microbiological or clinical)
~20% patients with ANC
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Epidemiology--NEJM, 1971;284:1061
Retrospective data have shown that
~ 50 % ofPseudomonas 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
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Epidemiology
Changing etiology of bacteremiaIATG-EORTC 1973-2000 trials of febrile neutropenia
Gram positive
dominant since mid
1980s1) More intensivechemoTx
Mucositis
2) In-dwelling catheters
Cutaneous-IV portal
3) Selective antiBx
pressureFluoroquinolones
Co-trimoxazole
4) Antacids
Promote oro-
oesophageal
colonisation withGPC
Viscoli et al, Clin Inf Dis;40:S240-5
Gram negative resurgence
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Duration of Neutropenia
< 7 days LOW risk
7 to 14 days INTERMEDIATE RISK
> 14 days HIGH RISK
D ti Of N t i
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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 14days of neutropenia (
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Common Microbes
Gram-positive cocci
and bacilli
Staph. aureus
Staphylococcusepidermidis
Enterococcus
faecalis/faecium
Corynebacteriumspecies
Gram-negative
bacilli and cocci
Escherichia coli
Klebsiella species Pseudomonas
aeruginosa
FUNGI
Candida- Non
albicans emerging
Aspergillus >> in
HSCT
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Initial evaluation
Ensure Hemodynamic Stability and No NEWORGAN DYSFUNCTION
History
Underlying disease, remission and transplantstatus- spleen +/-
Chemotherapy
Drug history (steroids, any previous antibiotics)
Allergies
Focused Review of systems
Transfusions Can cause fevers
Lines or in-dwelling hardware
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Splenectomy
THINK Strep.Pneumoniae
Neisseria meningitidis
Hemophilus Influenzae
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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 !
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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 zosterreactivation / Petechial rashes all arecommon in these patients)
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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 soressend 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
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Lumbar puncture-
Examination of CSF specimens is not
recommended as a routine procedure
but should be considered if a CNS
infection is suspected andthrombocytopenia is absent or
manageable.
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Skin lesions
Aspiration or biopsy of skin lesions
suspected of being infected should be
performed for cytologic testing, Gram
staining, and culture
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IMAGING in FN
CXR if Symptomatic or if out pt Rxconsidered
High resolution CT Chest Indicated ONLYif persistent fevers with pulmonary
symptoms after initiation of empiric Abx CTA if suspect PE
CT abdomen for Necrotizing Enterocolitisor Typhilitis
CT brain R/o ICH / MRI of the spine orbrain - more for evaluation of metastaticdisease than FN
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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
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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
HIGH risk Patients
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a Concomitant condition of significance (e.g.,shock, hypoxia, pneumonia,
or other deep organ infection, vomiting, or diarrhea).
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Risk model
Model 2(Klatersky et al MASCC 2000 J Clin Onc)
No or Mild symptoms 5
Moderate symptoms 3No Hypotension 5
No COPD 4
Solid tumour / 4
Haem malignancy
(no fungal infection)
Outpatient 3No dehydration 3
Age 20
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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
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If inpatient and high risk
EMPIRIC ANTIMICROBIAL
THERAPY after Blood
Cultures.Must be initiated within 1
hour
THREE h f IV
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THREE approaches for IV
EMPIRIC therapy IV MONO THERAPY
IV DUAL THERAPY
COMBINATION THERAPY
Mono or dual therapy + VANCOMYCIN
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Monotherapy IV
1. Extended spectrum Antipseudomonal
Cephalosporins
Cefepime
Ceftazidime
2. Carbapenem
ImipenemCilastatin
Meropenem
3. AntiPseudomonal PCN
Piperacillin- Tazobactam
Ticarcillin- Clavulanic acid
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DUAL therapy
1. an aminoglycoside
plus
an antipseudomonal penicillin
(with or without a beta-lactamase
inhibitor)
or
an extended-spectrum
antipseudomonal cephalosporin,
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Dual therapy
(2) ciprofloxacin plus anantipseudomonal penicillin.
Indications
Unstable patient
H/O P. aeruginosa colonization orInvasive disease
5 I di ti f
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5 Indications for
Vancomycin1. clinically suspected serious catheter-related
infections
2. known colonization with penicillin- and
cephalosporin-resistant pneumococci orMRSA,
3. positive results of blood culture for gram-positive
4. hypotension or other evidence of cardiovascular
impairment
5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole
i i t t
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vancomycin resistant
enterococcus Linezolid
Daptomycin (avoid for pneumonia)
Quinopristin- Dalfopristin
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PCN allergy
NON ANAPHYLACTIC
If not allergic to cephalosporins
~ Cefepime
ANAPHYLACTIC and allergic to
cephalosporins-
~Aztreonam +/- Aminoglycoside or a FQ
+/- Vancomycin if indicated
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MAINTAIN BROAD
SPECTRUM ACTIVITY
FOR A MINIMUM OF 7
DAYS OR UNTIL ANC
>500
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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, nodisease focus, mucous membranes, skin intact, no catheter siteinfection, no invasive procedures or ablative therapyplannedcease antibiotics and observe
When temperatures do not
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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
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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
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ANTI FUNGALS
AMPHO B IV drug of choice forhigh
risk patients
Alternative options
FLUCONAZOLE
ITRACONAZOLE
ECHINOCANDINS
Voriconazole is NOT FDA approved for
empiric therapy for persistent fevers in
FN
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Fluconazole ~ candida
Fluconazole
acceptable if NO
Moulds and Resistant
Candida
( C. K rusei 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.
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Itraconazole
In a recent controlled study of 384
neutropenic patients with cancer,
itraconazole and amphotericin B were
equivalent in efficacy as empiricalantifungal therapy.
FOR BOARDS use AmphoB OR
Itraconazole- hopefully should not askyou to choose between Itraconazole and
Ampho B
f
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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&1094,2005NEJM 353:977,988&1052,2005
Use of Antiviral Drugs
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Use of Antiviral Drugs
Antiviral drugs are not recommended forroutine use unless clinical or laboratory
evidence of viral infection is evident.
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Granulocyte Transfusions
Granulocyte transfusions are not
recommended for routine use.
Use of Colony-Stimulating Factors
Use of colony-stimulating factors isnot routine but should be
considered in certain cases with
predicted worsening of course.
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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
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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 withincreased Pseudomembranous colitis.
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Special Situations
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Neutropenic Enterocolitis or
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Neutropenic Enterocolitis or
Typhilitis Inflammatory process involving colon
and/orsmall bowel
ischemia, necrosis, bacteremia
( translocation from gut) hemorrhage,and perforation.
Fever and abdominal pain ( typically
RLQ). Bowel wall thickening on
ultrasonography or CT imaging.
T t t
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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.
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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
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H/O leukemia and
prolonged antibiotic therapy
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Angioinvasive Aspergillosis
Confirm with Biopsy
Aggressive Antifungal Therapy
Voriconazole (Drug of Choice)
Caspofungin FDA approved for Ampho andVoriconazole refractory Aspergillus.
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Case 1- Mr. Thomas June 20th 2009 diagnosed AML
June 21st 2009 R subclavian
Hickman placed and Chemotherapyinitiated
Remission Induction S/P 7+ 3 regimenCytarabine (Ara C) and Daunorubicin
June 28th 2009 - last dose ofchemotherapy.
July 10th 2009 - Febrile Neutropenia
ANC 280 ANC < 500 last 2 days
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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
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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
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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 donext?
A Stop Cefepime
B Add G- CSFC Continue Cepepime
until ANC > 500 or
a minimum of 7
days.D Continue
Vancomycin for a
total of 7 days.
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Remember for boards
Do not order CT scan in a neutropenicpatient with a normal CXR.
In clinical practice if patient remains
febrile for 3 to 5 days then the next stepis HRCT. ( 50 % of patients with +
imaging have a normal CXR)
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Conclusions
Febrile Neutropenia is a seriouscomplication 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.