This document discusses febrile neutropenia in a patient with acute myeloid leukemia (AML) who has recently undergone chemotherapy. The patient presents with a fever of 38°C. Key details include that the patient's absolute neutrophil count (ANC) is very low at 0.7 with 38% segments and 2% bands, indicating severe neutropenia. Management of febrile neutropenia depends on risk stratification based on factors like neutrophil count, expected duration of neutropenia, and presence of comorbidities. Initial evaluation includes blood cultures, screening for potential infection sites, and empiric intravenous antibiotics.

1. Hemang Mendpara
DNB trainee pediatrics
Choithram hospital indore

2. Why is this an Oncologic
emergency ??

3. 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

4. Case 1
July 10th
2009 - NF 1
You are asked to attend a call at 5:00am
by the nurse taking care of master harsh
on 2 AB
He spiked a fever of 38° C (100.4°F) one
hour ago.
-There is no order for acetamenophen.

5. ~ 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 paracetamol and take the next page.
OR…..

6. OR
 If you are alert, you think…
Am I missing febrile
Neutropenia???

7. 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?

11. 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

12.  You request her to repeat the
temperature and she reports 38. 2° C
(100.8 °F)

13. 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.

14. Definition of Neutropenia
 ANC ≤ 500/mm3 or
 ≤ 1000/mm3 and predicted decline to ≤ 500/mm
~ Clin Inf Dis, 2002;34:730-51

15. ANC : Master harsh
 WBC 0.7
 Segs = 38%
 Bands = 2%

16. 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)

17. calculation

18. 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

19. 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

20. Risk of Infection as Absolute Neutrophil Count Declines

21. Epidemiology
 Up to 60% febrile neutropenia
episodes = infection
(microbiological or clinical)
 ~20-30% patients with ANC
<100 cells/mm³ with febrile
neutropenia episodes have
bacteremias.

22. 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

23. Epidemiology
 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
Viscoli et al, Clin Inf Dis;40:S240-5Viscoli et al, Clin Inf Dis;40:S240-5
Gram negative resurgence

24. Duration of Neutropenia
 < 7 days LOW risk
 >7 days HIGH RISK
30% devlop fever or infection when neutropenia last <7 days as compared to
almost 100% when it remains low for >7 days

25. 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%

26. 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

27. 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

28.  Splenectomy
THINK
Strep. Pneumoniae
Neisseria meningitidis
Hemophilus Influenzae

29. Exam (be prepared to find no
signs of inflammation)
 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 !

30. 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)

31. 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

32. 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.

33. Skin lesions
 Aspiration or biopsy of skin lesions
suspected of being infected should be
 performed for cytologic testing, Gram
staining, and culture

34. 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
 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

35. Stratify risk of complications
1. Neutropenia
⇑ with severity of neutropenia (< 100/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

36. • Profound Neutropenia (≤100 cell/mm3
) anticipated to extend (>7
days)
• presence of co-morbid condition eg.
Hemodyenamic instability
Oral or gastrointestinal mucositis that interfere with swallowing
or cause severe diarrhoea
GI symp eg. Nausea, vomit, abd pain, diarrhoea
Neurological or mental status change of new onset
Intravascular catheter infection, catheter tunnel infection
New pulmonary infiltrates or hypoxemia, underlying chronic
lung disease
•Evidence of hepatic insufficiency (defined as aminotransferase
levels >5 time normal values) or renal insufficiency (defined as a
creatinine clearance of ,30 mL/min)
HIGH risk Patients

37. 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
Multinational association of supportive care in cancer risk index score

38. 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
“Oral treatment is not indicated in children-IAP”

39. If inpatient and high risk
 EMPIRIC ANTIMICROBIAL
THERAPY after Blood Cultures.
Must be initiated within 1 hour
– surviving sepsis guideline

40. THREE approaches for IV
EMPIRIC therapy
 IV MONO THERAPY
 IV DUAL THERAPY
 COMBINATION THERAPY
Mono or dual therapy + VANCOMYCIN

41. Monotherapy IV
1. Extended spectrum Antipseudomonal
Cephalosporins
• Cefepime
• Ceftazidime
2. Carbapenem
• Imipenem –Cilastatin
• Meropenem
2. Anti –Pseudomonal PCN
• Piperacillin- Tazobactam
• Ticarcillin- Clavulanic acid

42. DUAL therapy
1. Gm –ve : B lactum / carbapenem +
aminoglycoside / fluoroquinolones
2. Pneumonia : B lactum / carbapenem +
aminoglycoside / antipseudomonal FQ 10-14d
 Oral ulcerations or esophagitis = HSV or
Candida esophagitis infections in high-risk
patients, so empirical acyclovir and/or
fluconazole or another antifungal

43. 6 Indications for
Vancomycin
1. clinically suspected serious catheter-related infections / skin
soft tissue infection
2. known colonization with penicillin- and
cephalosporin-resistant pneumococci strep. Viridance or
MRSA, ( FOR VRE add linezolide)
3. positive results of blood culture for gram-positive
4. Hemodynamic instability ie. hypotension or other evidence of
cardiovascular impairment
5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole
6. Pneumonia documented radiographycally

44. vancomycin resistant enterococcus
 Linezolid (bone marrow suppression)
 Daptomycin ()
 Quinopristin- Dalfopristin (severe
arthralgia)
VRE is an independent risk factor for death

45. PCN allergy
 NON – ANAPHYLACTIC
If not allergic to cephalosporins
~ Cefepime
 ANAPHYLACTIC and allergic to
cephalosporins-
~Aztreonam +/- Aminoglycoside or a FQ
+/- Vancomycin if indicated

46. Fever (>38.3o
C and neutropenia <0.5*109
cells / L)
Low risk
Anticipated neutropenia ≤ 7 days
Clinically stable and no comorbid cond
high risk
Anticipated neutropenia ≥ 7 days
Clinically unstable and and
other medical comorbid cond
OUTPATIENT ANTIBIOTIC
-oral regimen if able to
tolerate and absorb
-Availability of care giver
Telephone and transportation
-Pt, physician decision
IN PT IV ABS
-documented infection
requiring IV abs
-Gastro intolerence
- Pt, Physician decision
IN PT IV ABS
Empirical antibiotic
monotherapy (any of below)
-PIP-TAZ
-Carbapenem
-Ceftazidime
- Cefepime
Oral ciplox + amoxy
clav
If responding and
criteria met for OPD mx
Observe 4-24 hours in clinic to ensure that
empirical abs tolerated and pt remains
stable prior to discharge for OPD therapy
Adjust ABS acc to
clinical lab and imaging
reports

47.  Vanco or linezolid for cellulitis or
pneumonia
 Add amino glycoside and switch to
carbapenem for pneumonia or gm-ve
bacteremia
 Metronidazole for abdominal symp or
suspected C. Difficle infection

50. Antibiotic and anti fungal
prophylaxis
 Not for low risk pt
 Fluoroquinolone prophylaxis should be considered for
high-risk patients with expected durations of prolonged and
profound neutropenia (ANC <100 cells/mm3 for .7 days) (BI).
 Levofloxacin = ciprofloxacin
 FQ does not need addition of GM+ve coverage

51.  Allo HSCT/ intensive remission induction / salvage induction agent :
Prophylaxis against Candida infection is recommended.
Fluconazole, itraconazole, voriconazole, posaconazole, micafungin,
and caspofungin are all acceptable.
 invasive Aspergillus infections with posaconazole should be
considered for selected patients >13 years of age who are
undergoing intensive chemotherapy for hematological melignancy in
whom the risk of invasive aspergillosis without prophylaxis is
substantial
 a mold-active agent is recommended in patients with prior invasive
aspergillosis (A-III), anticipated prolonged neutropenic
periods of at least 2 weeks (C-III), or a prolonged period of
neutropenia immediately prior to HSCT (C-III).
Antibiotic and anti fungal
prophylaxis

52. Anti viral prophylaxis
 HSV sero positive pt undergoing transplant
 Yearly inactivated influenzae vaccination to all > 7 days after or > 2
wk prior to chemo therapy
 Treat influenzae with neuraminidase inhibitor in outbreak.

53. G-CSF /GM CSF
 Prophylactic use of CSF should be considered
for patients in whom the
 anticipated risk of fever and neutropenia is
>20% (A-II).
 CSFs are not generally recommended for
treatment of established fever and neutropenia

55. 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

56. Summary of stopin abx
 Documented Infection
10-14 days/ till ANC>500
Clinical and micro settled
 Unexplained Fever in Low-Risk Patients
 An ANC >500 cells/mm3 if cultures are negative at 48 h and
patients remain afebrile for at least 24 h
 Daily increase in the absolute phagocyte count (bands and mature
neutrophils combined), the absolute monocyte count, or the
reticulocyte fraction
 in low risk patients who have defervesced after 3 days of empirical
antibiotic therapy, evidence of imminent marrow recovery may
direct cessation of broad-spectrum antibiotics prior to the ANC
reaching 500 cells/mm3

57.  Unexplained high risk
 Early discontinuation of antibiotic therapy while fever and
neutropenia both persist is strongly discouraged for high-risk
patients.
 Some experts advocate that patients with unexplained
fever who remain afebrile for 4–5 days may have empirical
antibiotics switched back to fluoroquinolone prophylaxis for
the remaining duration of neutropenia

58. 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

59. 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

60. ANTI FUNGALS
 AMPHO B IV drug of choice for high
risk patients
Alternative options
 FLUCONAZOLE
 ITRACONAZOLE
 ECHINOCANDINS
 Voriconazole

61. 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.

62. 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

63. CRBSI
 Differential time to positivity (DTP) .120 min of qualitative blood cultures
performed on specimens simultaneously drawn from the CVC and a vein
suggests a central line–associated blood stream infection (CLABSI) (A-II).
 For CLABSI caused by S. aureus, P. aeruginosa, fungi, or mycobacteria,
catheter removal is recommended in addition to systemic antimicrobial
therapy for at least 14 days (A-II). Catheter removal is also recommended for
tunnel infection or port pocket site infection, septic thrombosis, endocarditis,
sepsis with hemodynamic instability, or bloodstream infection that persists
despite >72 h of therapy with appropriate antibiotics (A-II).
 For documented CLABSI caused by coagulase-negative staphylococci, the
catheter may be retained using systemic therapy with or without antibiotic
lock therapy (B-III).
 Prolonged treatment (4–6 weeks) is recommended for complicated CLABSI,
defined as the presence of deep tissue infection, endocarditis, septic
thrombosis (A-II) or
 persistent bacteremia or fungemia occurring .72 h after catheter removal in a
patient who has received appropriate antimicrobials (A-II for S. aureus, C-III
for other pathogens).
 Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis
with chlorhexidine during CVC insertion are recommended for all CVC
insertions (A-I).

64. And above all of these….
 Hand hygiene
 Standard barrier precautions
 Isolation and air exchange room
 >12 air exchanges/h and high-efficiency particulate air (HEPA)
filtration (A-III).
 Plants and dried or fresh flowers should not be allowed in the rooms
of hospitalized neutropenic patients (B-III).
 Hospital work exclusion policies should be designed to
encourage health care workers (HCWs) to report their illnesses
or exposures (A-II).

65. 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.

66. Special Situations

68. 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.

69. 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.

70. 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.

71. Angioinvasive Aspergillosis
 Confirm with Biopsy
 Aggressive Antifungal Therapy
Voriconazole (Drug of Choice)
Caspofungin FDA approved for Ampho and
Voriconazole refractory Aspergillus.

72. Case 1- Master harsh
 June 20th
2009 – diagnosed AML
 June 21st
2009 – R jugular
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

73.  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

74. 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

75. Cefepime and Vancomycin are
initiated
 Blood cultures are +
for MRSA 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.

76. 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)

77. 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.