1. DR INNOCENT AGABA
DEPARTMENT OF PAEDIATRICS
MAUTH YOLA
31st May,2023
PATHOPHYSIOLOGY AND
MANAGEMENT OF FEBRILE
NEUTROPAENIA

2. OUTLINE
 INTRODUCTION
 EPIDEMIOLOGY
 DEFINITION
 PATHOPHYSIOLOGY
 CLINICAL FEATURES
 DIFFERENTIAL DIAGNOSIS
 MANAGEMENT
 FURTHER CONSIDERATIONS
 CONCLUSION
 REFERENCES

3. INTRODUCTION
 The basis of treatment of any malignancy includes aggressive
therapies such as radiation or chemotherapy that targets
rapidly dividing tumor cells.
 Because of the lack of specificity, unwanted secondary effects
arrests cell division in other cell lines, including those with a
rapid turnover such as in the bone marrow.
 Despite major advances in prevention and treatment, FN
remains one of the most frequent and serious complications
of cancer chemotherapy.
 Physicians must be keenly aware of the infection risks,
diagnostic methods, and antimicrobial therapies required for
management of febrile patients through the neutropaenic
period.

4. DEFINITION
 Defined as:
 FEBRILE
*Single temperature of > 38.30c
OR
sustained temperature of > 38.0 for at least one hour.
• NEUTROPAENIA
*Absolute Neutrophil Count (ANC) of less than 0.5 X 109/L (
<500cells/mm3)
OR
1.0 x 109/L with a predicted decrease to < 0.5 X 109/L
within the next 48hrs
• FEBRILE NEUTROPENIA (FN) is an oral temperature of ≥ 38.3 °C
or two consecutive readings of ≥38.0 °C for 2 hr and an absolute
neutrophil count (ANC) of < 0.5 × 109/l, or expected to fall below
0.5 × 109/l .
 ANC= Total white blood cell count(cells/mm3) x (percent neutrophils
+ percent Bands) ÷ 100

5. EPIDEMIOLOGY
 Most Chemotherapy regimens are associated with 6-8 days of
neutropaenia.
 Mortality from untreated FN ranges from 2 -21%
 FN is observed in approximately 8 cases per 1000.
 10 – 50% of patients with solid tumours and 80% of those with
hematological malignancies will develop fever during >1
chemotherapy cycle associated with neutropaenia
 A study done in Pakistan showed that ALL was the most frequent
underlying malignancy (84.3%) and the highest FN episodes
(72.1%) occurred during the induction phase treatment
 A study in East Africa revealed that Acute lymphocytic leukemia
(ALL) was the most frequent diagnosed cancer type among
febrile neutropenic patients in more than half of the participants.
 Clinically documented infections occur in 20 – 30% of febrile
episodes ; common sites of tissue based infection include the
intestinal tract,lungs and Skin.

6. EPIDEMIOLOGY CONT…
 Substantial fluctuation in the epidemiological
spectrum of bloodstream isolates obtained from
febrile neutropaenic patients has occurred over the
past 40 years
 During the 1960’s and 1970’s,gram negative
pathogens predominated.
 During the 1980’s – 1990’s,gram positive organisms
became more common because of increased use of
indwelling plastic venous catheters which allow for
colonization by and entry of gram positive skin flora.
 The majority of patients who develop fever during
neutropaenia have no identifiable site of infection and
no positive culture results.

7. ETIOLOGY
 Most infections are bacterial, but viral or fungal
etiology are possible.
 Coagulase Negative Staphylococci (CONS)is the
most common blood isolate.
 Recent trends have shown gram positives
organisms accounting for more than 50% of blood
cultures in children undergoing chemotherapy.
 Drug – resistant gram negative bacteria species are
causing an increasing number of infections.
 Fungi are rarely identified early in the course of
neutropaenia; can be seen in cases of prolonged
neutropaenia.

8. ETIOLOGY
 BACTERIA
Gram negative enteric organisms : Escherichia
Coli, Klebsiella pneumoniae, Enterobacter spp,
Pseudomonas aeruginosa
Gram positive organisms : Staphylococci spp,
streptococci spp, clostridia spp
• FUNGI
Candida spp ( C. Albicans, C. tropicalis )
Aspergillus spp (A. fumigatus, A. flavus)

9. PATHOPHYSIOLOGY - FEVER
 Fever is defined as a single oral temperature
measurement of >38.30c or a temperature of >38.0
sustained over a 1 hour period.
 Site of measurement, age of patient, time of day e.t.c
affect the value obtained.
 Fever occurs when either endogenous or exogenous
pyrogens cause an elevation in the body's
thermoregulatory set-point.
 Fever during chemotherapy induced neutropaenia may be
the only indication of a severe underlying infection
because signs and symptoms of inflammation typically are
attenuated.
 NB: Oral temperatures are usually 0.3 – 0.6oc higher than
axillary temperatures.

10. Pathophysiology - Fever

12. Pathophysiology - Neutropaenia
 Leukopoeisis

13. Pathophysiology - Neutropaenia
 Functions of Neutrophils

14. Pathophysiology - Neutropaenia
 Neutrophil life cycle

15. Pathophysiology - Neutropaenia

16. PATHOPHYSIOLOGY -
NEUTROPAENIA
 Profouned Neutropaenia : ANC < 100
 Severe Neutropaenia : ANC < 500
 Prolonged Neutropaenia : > 7 days
 Chronic neutropenia : Neutropenia for > three
months:
 Isolated Neutropenia : Neutropenia without
associated anemia and/or thrombocytopenia:
 Granulocytopenia : Reduced number of
neutrophils, eosinophils, and basophils:

17. Pathophysiology OF FN
 Bone marrow infiltration by malignancy
 Chemotherapy induced pancytopaenia
 Defective humoral and cellular defects
 Mucositis
 Central Venous catheter infections
 Anorexia

19. CLINICAL FEATURES
 Detailed history & physical examination with special
attention to clues suggesting etiology or focus of
infection,and also try to identify any features that
may help risk stratify the patient.
 Factors which contribute to occurrence of FN in
pediatric cancer patients include age of child,
duration of neutropenia, ANC value, co-morbidities,
type of cancer and its stage, complication of
chemotherapy, identified pathogens, the severity of
vital signs.
 Fever is typically the first manifestation of a severe
infection, especially in a neutropaenic patient.
 Attention to signs of shock, hypoxia or deep organ
infections is essential.

20. HISTORY
 Presenting illness
 Specific type of cancer
 Chemotherapy treatment (type and number)
 Medication use (including prior broad spectrum
antibiotics)
 Previous history of infections, especially with
bacterial-resistant organisms,
 Allergies, should be noted to guide your therapy
 Co-morbidities

21. EXAMINATION
 Seek for subtle signs
 Pain and tenderness may be the only indicators of
infection.
 Periodontium,pharynx,perineum,eyes,lungs,esopha
gus
 Rectal temperature measurements (and rectal
examinations) are avoided during neutropaenia to
prevent colonizing gut organisms from entering the
surrounding mucosa and soft tissues.
 Use of axillary temperatures is discouraged
because they may not accurately reflect core body
temperature.

22. INVESTIGATIONS
 Blood cultures - Qualitative vs quantitative
*Lumens of central venous catheters
*Peripheral blood culture from two different sites
 Imaging
*CXR only in symptomatic patients
* CT in prolonged neutropaenia
• Additional diagnostic and supportive tests
*Urinalysis
*CBC
*LFT
*Serum E/U/Cr
*CSF Analysis

23. DIFFERENTIAL DIAGNOSIS
 Transfusion reaction
 Medication allergies and toxicities
 Tumor-related fever
 Thrombophlebitis
 Resorption of blood from large hematoma
 Viral infections
 Invasive fungal infections

24. MANAGEMENT
 Guidelines
*2017 International paediatric fever and Neutropaenia Guidelines Panel
*2011 Interntional Diseases Society of America(IDSA)
 Risk stratification
*MASCC (Multinational Association for supportive Care in cancer Risk –
index score)
*The Clinical Index of Stable Febrile Neutropenia Score
* Clinical assesment
 This is a means to determine which patients require prolonged
hospitalization and which may be candidiates for oral or once daily IV
reimens and/or for early discharge from the hospital to complete the
antibiotic course as outpatients.
 The classification of FN in terms of the risk of infection helps to choose
antimicrobial therapy, in defining the route of administration, the possibility
of outpatient treatment and the probable etiology

25. MASCC Scoring Index
Characteristic/Score
The burden of illness: no or mild symptoms: 5
The burden of illness: none or mild: 5
The burden of illness: moderate symptoms: 3
The burden of illness: severe symptoms: 0
No hypotension (systolic BP greater than 90 mmHg): 5
No chronic obstructive pulmonary disease: 4
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*
 According to the MASCC scores, a patient with a score < 26 is to be
considered at low risk and treated as an outpatient, whereas a patient
with a score > 21 is at high risk and should be hospitalized

26. The Clinical Index of Stable Febrile
Neutropaenia Score
Characteristics/Score
ECOG performance status (greater than 2): 2
Chronic obstructive pulmonary disease (COPD): 1
Stress-induced hyperglycemia: 2
Chronic cardiovascular disease: 1
Monocytes less than 200 per mcL: 1
mucositis: 1
Interpretation
0-2: Consider outpatient management with oral
antibiotics
≥ 3: Inpatient management

27. CLINICAL ASSESMENT
*HIGH RISK
 Prolonged (> 7 days duration) and Profound neutropaenia (ANC
<100cells/mm3) OR
 Type of malignancy : AML,pre-B ALL,Burkitts
Lymphoma,progressive malignancy, relapse with Bone marrow
involvement
 Type of chemotherapy : HSCT, ALL Induction, Any chemo more
intensive than ALL maintenance therapy
 Presence of central venous catheter
 Age ≤ 5years
 Presence of hypotension,pneumonia,new-onset abdominal pain,or
neurological changes
 Laboratory : Hb : 7g/dl, Plt : 50,000/ul
 Imaging : New CXR changes
*LOW RISK
 Neutropaenia expected to last < 7 days
 No other abnormalities present

28. Principles of Treatment
 Treat as an EMERGENCY!
 Empiric broad-spectrum antibiotic therapy is the main
management initiated for the treatment of FN in patients
with cancer.
 Regimen MUST provide coverage against Pseudomonas
and at least some coverage for gram negative organisms.
 Inpatient vs Outpatient
 Oral vs Parenteral
 High risk vs Low risk
 Monotherapy vs Duotherapy
 Vancomycin ?
 Antifungal therapy?

29. INPATIENT vs OUTPATIENT
 Inpatient treatment recommended for;
1. All high risk patients
2. Low risk patients with the following conditions
*Presence of clear anatomic site of infection
*Cardiovascular comorbidities
*Severe thrombocytopenia(platelets < 10,000/mcl)
*Unable to swallow oral medications
*Concern for poor adherence to outpatient treatment
 Outpatient treatment recommended for;
* Low risk patients able to take oral medications
* Absence of above complications
* Ease of monitoring and follow up

30. ORAL VS PARENTERAL
 Flouroquinolones +/- Amoxicillin-clavulanate
 Consider oral if child is able to reliably tolerate
oral antibiotics
 Presents a challenge in the presence of mucositis
and/or impaired G.I absorption.
 Some centres allow outpatient mgt of selected
low risk children after a single dose of Parenteral
antibiotics such as Ceftazidime and then
discharged on oral antibiotic such as ciprofloxacin

31. HIGH RISK VS LOW RISK
• HIGH RISK
Monotherapy with an antipseudomonal beta lactam:
*IV Cefepime 50mg/kg/dose 8hrly(Max dose 2g/dose)
*IV Meropenem 20mg/kg/dose 8hrly(Max 1g/dose)
Addition of a second gram negative agent or glycopeptides:
*patients who are clinically unstable
*Suspicion of a resistant infection
*Centers with a high rate of resistant pathogens
 LOW RISK
Oral antibiotics can be considered if :
* the child is able to tolerate the route of administration reliably
* infrastructure is in place to ensure careful monitoring and
follow up

32. MONOTHERAPY VS
DUOTHERAPY
MONOTHERAPY
• Antipseudomonal penicillin monotherapy is non-inferior to
aminoglycoside containing regimens for initial management,and has
less toxicity.
DUOTHERAPY
 AMINOGLYCOSIDES + Antipseudomonal
penicillin,cefepime,ceftazidime or
carbapenems.
 Advantages:
*Synergestic effect
*Decrease in emergence of drug resistance
 Disadvantages:
*Ototoxicity
*Nephrotoxicity

33. VANCOMYCIN?
 IDSA recommendation is that Vancomycin should only be
added to the initial regimen if:
* Catheter related infections
* Severe mucositis
* ß – lactam resistant streptococcus pneumoniae
* hypotension or other signs of sepsis
* Known colonization with MRSA
 Empiric duotherapy with Vancomycin + Ceftazidime has been
extensively studied in neutropaenic patients and found to be
safe and efficacious
 Unwarranted overuse increases the risk of Vancomycin
resistant enterococcus.
 Discontinued after 48hrs if clinical course is stable and gram-
positive organisms are not isolated

34. ANTIFUNGAL THERAPY
• Fungal superinfection may affect 9 – 31% of
patients with prolonged Neutropaenia
• Caspofungin,Voriconazole or liposomal
amphotericin B
• Consider antifungal therapy if:
*Prolonged febrile neutropaenia
*AML,Relapsed acute Leukemia
* Allogeneic HSCT
* Receiving high dose corticosteroids

35. Fever(temperature >38.3oc) + Neutropaenia
(<500neutrophils/mm3)
Obvious catheter – related infection
Known colonization with MRSA or B-lactam resistant
pneumococcus
Severe Mucositis
Hypotension or sepsis syndrome
Positive blood culture for gram positive organism (pending
susceptibility testing)
Vancomycin not
needed
Duotherapy
Cefepime,
Ceftazidime
Or
Carbapenem
Aminoglycoside
+
Antipseudomonal
penicillin,
cefepime,ceftazidime,or
carbapenem
Vancomycin needed
Vancomycin
+
Cefepime,ceftazidime.or
carbapenem
+/-
aminoglycoside
NO YES
Monotherapy Vancomycin +

36. Treatment Monitoring
 3 – 5 days,
 The condition of the patient is the primary determinant of
further therapy:
*Absence of presenting signs & symptoms of sepsis
*No evident source of infection
*Clinical improvement
*negative cultures after 48hours
*ANC > 100/mm3
Consideration
 Change to an appropriate oral antibiotics i.e Cefixime.
 Discharge to continue parental medications at home.

37. Afebrile within 1st 3 days of
treatment
No etiology
identified
Low
risk
High risk
Consider
discharge
Continue antibiotic
therapy
Etiology identified
Adjust to most
appropriate treatment

38. MONITORING CONT…
 After the 5th day
 Antibiotics may be discontinued after the 7th day if :
*Patient remains afebrile
*If ANC > 500/mm3
*Evidence of bone marrow recovery
 Continue parenteral Antibiotics if:
* ANC remains < 100/mm3
*Ongoing mucositis
* factors predisposing to recurrent
infections(even if afebrile)

39.  After the 5th day
 If fever continues beyond 5 days, actively consider:
*Non bacterial infection
*A drug resistance organism
*Poorly accesible focus of infection(e.g Abscess)
*Inadequate dosing of antimicrobials
*non-infectious cause of fever
Considerations
 Re-examine thoroughly
 Repeat blood cultures + fungal cultures
 Imaging studies
 Continue antibiotics for at least 2 weeks
 Commence antifungal therapy

40. Persistent fever during
treatment
No etiology identified
Reassess patient on Day 4 to
5
Clinically stable:
Continue initial
antibiotics
Unstable or toxic :
Change antibiotics
If no change in patient,
consider stopping
Vancomycin(if used
initially)
If progressive disease, add
vancomycin and consider
other
changes(anaerobes,entero
cocci)
Febrile through day 5 –
7
Resolution of
neutropaenia not
imminent
Add Antifungal therapy
with or without change
in Antibiotics

41. DURATION OF TREATMENT
 Traditionally,broad spectrum antibiotic therapy is
continued until the ANC has returned to >0.5 x
109/L .
 Antibiotics may be discontinued after 7 days(as
earlier explained)
 Persistent fever in patients with ongoing
neutropaenia requires treatment for a minimum of
2 weeks.

42. OTHER CONSIDERATIONS
 The use of Colony GSF
*Not recommended routinely
*Can shorten the duration of neutropaenia
*Does not decrease mortality
 Granulocyte Infusions
 Use of probiotics/prebiotics
 Prophylactic antimicrobial therapy

43. CONCLUSION
 Currently,appropriate administeration of
antibacterial and antifungal antibiotics remain
standard of care.
 Each institution must develop a plan of care,
based on local epidemiology and resistance
pattern of infection.
 Definitive guidelines for risk stratification in the
paediatric population as compared to adults are
not available.

44. REFERENCES
 Andrew YK. Prolonged febrile neutropaenia in the paediatric
patient with Cancer. ASCO Educational book 2012; Vol 32:
565 – 569
 Alia Z. Febrile Neutropaenia current guidelines for Children,
January,2016. SIOP PODC Supportive care Education.
 Davis K,Wilson S. Febrile Neutropaenia in paediatric
oncology. Paediatr Child Health (Oxford). 2020 Mar;30(3):93
– 97.
 Rudolph M., Rudolph CD, Paller,Hostettter MK,Lister G. &
Siegel Nj (2011)Rudolphs Textbook of Paediatrics 22nd Ed.
McGraw Hill