Decrease in the absolute number of circulating segmented neutrophils and band cells in peripheral blood Absolute Neutrophil count

1. Febrile Neutropenia
Presented By
Dr. Mukesh Sah
@mukeshdelano 1

2. @mukeshdelano 2

3. Febrile Neutropenia
Considered primary cause of
mortality in 36% of cancer patients
Considered secondary cause of
mortality in 68% of cancer patients
It is the most common cause of
mortality and morbidity
@mukeshdelano 3

4. Incidence of Febrile
Neutropenia
Incidence of Febrile Neutropenia
Induction-remission for AML 70-90%
Elderly patients receiving
CHOP
35-45%
Mortality Estimates from Febrile Neutropenia
Hematological malignancies 11%
Gram-positive bacteremia 5%
Gram-negative bacteremia 18%
@mukeshdelano 4

5. Introduction
Most abundant
type of WBC
First
responders of
inflammatory
cells
Short life
span of 4-5
days
Neutrophils
@mukeshdelano 5

6. Neutropenia
 Decrease in the absolute number of circulating segmented neutrophils and band
cells in peripheral blood
 Absolute Neutrophil count (ANC) = Total white blood cells/micro L * Percent
(PMNs + Band cells) /100
 At birth – predominant but rapid decrease begins at 12 hour through the 1st
week of life
 Infancy – 20-30% of TLC
 At 5 years – equal number of neutrophils and lymphocyte count
 In Adults – characteristic 70% predominance of neutrophils is usually attained
during puberty
@mukeshdelano 6

7. Pathophysiology
Neutropenia is most commonly seen as a result of cytotoxic therapy although
the ANC of individuals can drop significantly through cancer’s direct interaction
with hematopoiesis (e.g. in leukemia) or the bone marrow metastatic
replacement
When neutropenia is associated with an increase in the body temperature, the
patient has usually developed a pathological infection which is caused in 33% of
the cases by pathogenic microorganisms
Exogenous pyrogens induce several cytokines which activate immune
responses, and produce fever.
@mukeshdelano 7

8. Types
Neutropenia Absolute Neutrohil count
Normal 1500 -8000 /cu mm
Neutropenia < 1500 /cu mm
Mild 1000-1500 /cu mm
Moderate 500-1000/ cu mm
Severe < 500/ cu mm
Profound < 100/cu mm
Prolonged Neutropenia – Lasting more than 7 days
Chronic Neutropenia –last more than 3 months
Functional Neutropenia: Impaired function of circulating neutrophils as seen in certain hematologic malignancies
Constitutional neutropenia is neutropenia of longstanding duration, typically since childhood
@mukeshdelano 8

9. What's febrile neutropenia?
• Fever: Single oral temperature ≥38.3°C or
persistent temperature ≥38.0 °C (100.4 F) for >1
hour OR Two consecutive temperature >38.3 °C in
a 12 hr period for at least 1 hr
• Neutropenia: ANC <0.5, or ANC <1.0 and a
predicted decline to <0.5 over next 48 hrs.
(ANC= absolute neutrophil count)
@mukeshdelano 9

10. @mukeshdelano 10

11. Initial investigations
History and physical exam
Lab assessments
Diagnostic imaging
Microbiologic evaluation
@mukeshdelano 11

12. History & physical examination
Differential CBC , RFT , LFT , Electrolytes & uric acid
At least 2 sets of blood cultures & culture specimens from sites
of suspected infection
Sputum culture
Urine analysis
CXR is indicated for patients with respiratory signs or symptoms
@mukeshdelano 12

13. Detailed H & P
History
Fever – onset, duration, severity
Chemotherapy regimen & last dose given
Vascular devices
Prophylactic antibiotic
Steroid use
Major comorbid illnesses
Recent hospitalization and antibiotics received
@mukeshdelano 13

14. Site specific H & P
Examinations
Eyes Conjunctivitis, Orbital cellulitis
Ear, Nose and Throat Otitis media, sinusitis, Tonsillitis,
Pharyngitis, Oral candidiasis
Teeth Dental caries/abscess
Respiratory system Pneumonia
Abdomen Diarrhea, Dysentery, Neutropenic
enterocolitis, Pseudomembranous
colitis
Perineum Perianal candidiasis, Perianal abscess
Skin Cellulitis, Abscess, Nodular or target
lesions, Varicells rashes
genitourinary Yeast Infections, UTIs
CNS Meningitis, Meningo encephalitis,
Cavernous sinus Thrombosis
@mukeshdelano 14

15. •Risk stratification
@mukeshdelano 15

16. Risk status Assessment
Low Risk High Risk
Outpatient at time of fever Inpatient at time of fever
No acute comorbid illnesses Significant medical comorbidity
Anticipated short duration of severe
neutropenia (<7 days)
Anticipated severe or prolonged
neutropenia (>7 days)
(absolute Neutrophil count [ANC] <100
cells/mm3)
No renal insufficiency CrCL <30 ml/min
No hepatic insufficiency Transaminases ≥5x ULN
Good performance status Uncontrolled/progressive cancer,
Mucositis grade 3-4
MASCC Risk Index score ≥21 MASCC Risk Index score <21
Complex infection
@mukeshdelano 16

17. What is MASCC
(The Multinational association for supportive care in
cancer Patient )
Prospectively validated tool to rapidly assess risk before access to neutrophil count.
criteria score
Burden of illness (No/Mild) 5
Burden of Illness (Moderate) 3
Burden of Illness (severe) 0
No Hypotension 5
No COPD 4
Solid tumor/Lymphoma
No previous fungal infection
4
No Dehydration 3
Outpatient status (onset of fever) 3
Age <60 years 2
Characteristic/Score
@mukeshdelano 17

18. Type of Cancer
Solid tumor 4
Lymphoma with previous fungal infection 4
Hematologic with previous fungal infection 4
No dehydration 4
Outpatient status (at the onset of fever) 3
Age less than 60 years 2
@mukeshdelano 18

19. The Clinical Index of Stable
Febrile Neutropenia Score
ECOG performance status (greater than 2) 2
Chronic obstructive pulmonary disease (COPD) 1
Stree-induced hyperglycemia 2
Chronic cardiovascular disease 1
Monocytes less than 200 per mcL 1
Grade greater than or equal to 2 mucositis 1
Interpretation
Characteristics/Score
0-2/Consider
outpatient
management with oral
antibiotics
Greater than or equal
to 3/inpatient
management
CISNE/Recommendation
@mukeshdelano 19

20. Low Risk Treatment
Low risk, adult patients
No focus of infection, hemodynamically stable
No systemic symptoms other than fever
No organ failure, pneumonia, soft tissue infection
Recovering bone marrow
Reliable patient
Hospital admission is required for persistent fever or signs and
symptoms of infection.
Vigilant observation
Access to medical care 24-7
Return to clinic if
1. Positive cultures
2. Persistent/recurrent fever (3-5 days)
3. Unable to tolerate PO regimen
Cipro 500 mg PO Q8h + amoxicillin-
clavulanate 500 mg PO Q8h
@mukeshdelano 20

21. @mukeshdelano 21

22. High risk treatment
Always cover pseudomonas
Monotherapy Meropenem
Cefefeme
Imipenem
Piperacillin – Tazobactam
Add Aminoglycoside if:
• Severe septic shock
• Evidence of P. Aoruginosa
@mukeshdelano 22

23. @mukeshdelano 23

24. Management
IV
Monotherapy
IV Dual
therapy
Combination
therapy
Mono or Dual Therapy + VANCOMYCIN
@mukeshdelano 24

25. IV combination Therapy
Advantages Disadvantages:
Synergistic effect against gram-neg Lack of activity against gram-pos?
Reduced emergence of resistance Toxicity
Intravenous PIPERACILLIN-TAZOBACTAM, OR
Intravenous IMIPENEM OR MEROPENEM, OR
Intravenous CEFEPIME OR CEFTAZIDIME
Aminoglycoside + (Any of above)
Ciprofloxacin + (Any of above)
First Line of defense
@mukeshdelano 25

26. Second line
Intravenous PIPERACILLIN-TAZOBACTAM, OR
Intravenous IMIPENEM OR MEROPENEM, OR
Intravenous CEFEPIME OR CEFTAZIDIME
+
Vancomycin
Third line
Colistin is reserved as third drug
If anaphylaxis allergy to beta-lactams, treat with
VANCOMYCIN + AMINOGLYCOSIDE + CIPROFLOXACIN
@mukeshdelano 26

27. IV Therapy Options:
Comparison
Piperacillin-tazobactam
Broad spectrum gram(-), gram(+) & anaerobic coverage
Use for intra-abdominal source
Not recommended for meningitis (poor CSF penetration)
Meropenem
Broad spectrum gram(-), gram(+) & anaerobic and ESBL
coverage
Use for intra-abdominal source
Preferred for meningitis/CNS infection
@mukeshdelano 27

28. IV Therapy Options:
Comparison
Imipenem-cilastin
Broad spectrum gram(-), gram(+) & anaerobic and ESBL
coverage
Risk of seizures in CNS malignancy or renal impairment
Ceftazidime
Poor gram(+) activity
Breakthrough streptococcal infections
No activity against anaerobes, enterococcus
Good CSF penetration
@mukeshdelano 28

29. IV Treatment Options:
Comparison
Aminoglycosides
Gram(-) coverage, synergy with beta-lactams against S.aureus and
Enterococcus
Nephrotoxicity, ototoxicity
Ciprofloxacin
Gram(-) and atypical bacterial coverage
No anaerobic coverage, less gram(+) activity than other options
Good clinical studies as empirical PO or IV therapy
Avoid in patients recently treated with quinolone prophylaxis
Levofloxacin: better gram (+) coverage but limited studies
available for use as empiric therapy.
@mukeshdelano 29

30. Vancomycin
Is not recommended as a standard part of the initial
antibiotic regimen for fever and Neutropenia
Clinical indications:
Catheter-related infection
Skin or soft-tissue infection
Pneumonia confirmed
Hemodynamic instability - Hypotension
Severe Mucositis
@mukeshdelano 30

31. @mukeshdelano 31

32. If an infection is documented, for
how long ABs should be continue?
Resolution of signs and symptoms of infection
Always treat 10-14 days for
Bloodstream infection
Soft tissue infection
Pneumonia
@mukeshdelano 32

33. If infection is undocumented, for
how long ABs should be continue?
Patient can be changed from IV to PO treatment if
a febrile after 3 days of therapy and clinically stable
Use fluoroquinolone (Levofloxacin ) for remainder
of neutropenia
@mukeshdelano 33

34. If no improvement?
Empericial antifungal coverage should be considered in patients
who have persistent fever after 4-7 days of broad-spectrum
antibacterial regimen and no identified fever source
Oral thrush, Mucositis : Mouthwash, Fluconazole
Esophageal lesions: Fluconazole
Sinus/nasal symptoms and suspicious CT/MRI: Amphotericin B
Pneumonia: voriconazole, amphotericin B
Empiric treatment required based on H&P as positive cultures
can take several days.
@mukeshdelano 34

35. Antifungals Added Later?
IDSA recommends consider antifungal if febrile
after 3-5 days and remains neutropenic
Amphotericin B is preferred
Fluconazole may be acceptable at institutions with
low rates of mold infections or drug-resistant
Candida species
@mukeshdelano 35

36. Antifungals Added Later?
NCCN recommends:
Add fluconazole if
• no prior azole antifungal prophylaxis,
• low risk for invasive aspergillosis and
• low rates of azole-resistant Candida.
Dosing:
• 150 mg PO x1 dose for vaginal candidiasis
• 200 mg PO daily x14 days for candidal pyelonephritis
• 800 mg x1 then 400 mg daily x14 days from first negative culture for
candidiasis (not recommended if received prophylaxis)
• 400 mg PO daily prophylaxis for neutropenic patients
@mukeshdelano 36

37. NCCN Recommends
Add voriconazole, liposomal amphotericin B or an echinocandin if
already exposed to an azole or known to be colonized with non-
albicans Candida.
Voriconazole 6 mg/kg IV q12h x2 doses then 4 mg/kg IV/PO q12h
Amphotericin B 3-5 mg/kg IV daily
Caspofungin 70 mg IV x1 then 50 mg IV daily; 70 mg IV daily for
aspergillosis
Continue until neutropenia has resolved, or for at least 14 days in
patients with a demonstrated fungal infection.
@mukeshdelano 37

38. When to Add Antiviral
Therapy
Oral vesicular lesions: HSV
Esophageal lesions: HSV, CMV
Skin lesions: VZV
Pneumonia: Influenza
CNS symptoms: HSV
@mukeshdelano 38

39. Antiviral Doses
Acyclovir
 Mucocutaneous HSV: 5 mg/kg IV Q8h
 Single dermatomal VZV: 800 mg PO 5x/day or 5 mg/kg IV Q8h
 Disseminated VZV or HSV: 10 mg/kg IV Q8h
Valacyclovir
 HSV or VZV treatment: 1g PO Q8h
Ganciclovir:
 CMV treatment: 5 mg/kg IV Q12h x2 weeks then 5 mg/kg IV Q24h x2-4 weeks
Acyclovir-resistant HSV: 40 mg/kg IV Q8h
CMV treatment: 90 mg/kg IV Q12h x2 weeks then 120 mg/kg IV Q24h x2-4 weeks
Oseltamivir:
Influenza: 75 mg PO Q12h
(reduced doses required in renal impairment)
@mukeshdelano 39

40. Assessment of Response
Daily assessment until afebrile and ANC >0.5
Fever
CBC
Renal function
Clinical Symptoms
@mukeshdelano 40

41. Duration of Therapy
Afebrile and ANC >= 0.5 x48 hrs:
Low risk patients, no source of infection identified: can discontinue abx
High risk patients or with documented infection: continue tailored therapy
>=7 days
Afebrile but ANC <0.5 after 5-7 days:
low risk: can discontinue abx
high risk: continue abx until ANC >0.5 or 14 days in pts not expecting ANC
recovery.
IDSA 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer
@mukeshdelano 41

42. Febrile:
Neutropenic: continue abx at least 14 days, reassess
for non-response
Non-neutropenic: discontinue abx 4-5 days after ANC
>0.5 if no source of infection identified
IDSA 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer
@mukeshdelano 42

43. Follow up for Non-
Responsive Patients
Febrile but otherwise stable
If non-neutropenic consider stop abx 4-5 days after ANC
>0.5
Consider antifungal therapy with activity against mold if
fever continuing ≥4-5 days.
Febrile and clinically unstable
Broaden coverage to include anaerobes, resistant gram
negative, resistant gram positive organisms
Ensure coverage of Candida
Consider antifungal therapy with activity against mold if
fever continuing ≥4 days of therapy
@mukeshdelano 43

44. Duration of Therapy for
Documented Infection
Aspergillus min 6-12 weeks
Viral:
HSV/VZV: 7-10 days
Influenza: ≥5 days
@mukeshdelano 44

45. @mukeshdelano 45

46. •Prophylaxis
@mukeshdelano 46

47. Indication of prophylaxis
Allogeneic hematopoietic stem cell transplant recipients.
Those undergoing intensive induction or salvage-induction
chemotherapy for leukemia
prolonged and profound neutropenia (ANC <100 cells/mm3
for >7 days)
@mukeshdelano 47

48. Drugs can be used
Abs Fluoroquinolone (Levofloxacin)
Antifungal Fluconazole, itraconazole, voriconazole and caspofungin are all acceptable
alternatives
Antiviral Acyclovir Herpes seropositive recieving agressives chemotherapy.
@mukeshdelano 48

49. What Is the Role of Growth Factors in
Management?
CSFs are not generally
recommended for
treatment of established
fever and neutropenia
CSF should be
considered as
Prophylactic only
@mukeshdelano 49

50. What environmental precautions
should be taken when managing FN?
Hand hygiene is the most effective means of preventing transmission of
infection in the hospital
Patients should be placed in private (ie, single patient) rooms with air
exchanges and particulate air filtration.
Plants and dried or fresh flowers should not be allowed
Encourage health care workers to report their illnesses or exposures.
@mukeshdelano 50

51. Hematopoietic growth factor for
Preventing Febrile Neutropenia
Administering more than 600 µg/day of granulocyte-
colony stimulating factor (G-CSF) prevents recurrence
of febrile neutropenia during chemotherapy
Higher dosing does not increase side effects
@mukeshdelano 51

52. Pegfilgrastim (Rx)
G-CSF (Filgastim) @ 2-5mcg/kg/day in addition to antibiotics
is useful with complicated febrile Neutropenia (Pneumonia,
Hypotension, Invasive fungal investion or MODS)
6mg SC once per chemotherapy cycle
@mukeshdelano 52

53. Advantages
More rapid Neutrophil recovery
shortens days of antibiotics use
Shortens length of hospital stay
Reduces mortality and morbidity
But G-CSF has no role in the management of children with uncomplicated neutropenia
@mukeshdelano 53

54. Adverse Effects
@mukeshdelano 54

55. @mukeshdelano 55