Febrile Neutropenia Final 7-29

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.

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Febrile Neutropenia Final 7-29

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