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Febrile neutropenia

Nadirah Rasyid Ridha

Divisi Hemato-Onkologi, Departemen Ilmu Kesehatan Anak,


Fakultas Kedokteran Universitas Hasanuddin/
RSUP Dr. Wahidin Sudirohusodo, Makassar
Fever??
• Fever: Single oral temperature
≥38.3°C or persistent temperature
≥38.0 °C for >1 hour.
Leukocyte
• Cells of the immune system that are involved in protecting the body
against both infectious disease and foreign invader
• Normal count 4,000 – 10, 000 mm3
• <4.000 mm3  leukopeni
• >10.000 mm3  leukocytosis
Neutropenia??
• Neutropenia: ANC <500 cells/mm3, or ANC <1000 cells/mm3
and a predicted decline to <500 cells/mm3 < over next 48 hrs.
(ANC= absolute neutrophil count)
• ANC: total Leukocyte x ( %neutrophil )
• Normal level of neutrophi 50%-70%
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
Epidemiology
• Up to 60% febrile neutropenia episodes = infection
(microbiological or clinical)

• ~20% patients with ANC <100 cells/mm³ with febrile


neutropenia episodes have bacteremias.
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
Duration of Neutropenia
• < 7 days LOW risk

• 7 to 14 days INTERMEDIATE RISK

• > 14 days HIGH RISK


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%
Common Microbes
Gram-negative
Gram-positive cocci and bacilli • bacilli and cocci
• Staph. aureus • Escherichia coli
• Staphylococcus epidermidis • Klebsiella species
• Enterococcus faecalis/faecium • Pseudomonas
• Corynebacterium species aeruginosa
FUNGI
• Candida- Non albicans
emerging
• Aspergillus
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
Febrile neutropenia
Investigation
• Complete Blood Count (with Differential)
-White cells, haemoglobin, platelets, Blood Smear
• Biochemistry
-Electrolytes, urea, creatinine, Liver function
• Microbiology
-Blood cultures (peripheral and all central line lumens)
-Oral ulcers or sores –send swabs ( Viral and fungal )
-Exit site swabs
-Wound swabs
-Urine Cultures
-Stool Cultures and CDiff Toxin/PCR
• Radiology
-Chest Xray +/- CT abdomen/pelvis
Site-Specific
• Oropharynx
• Respiratory system
• GI tract
• Skin
• Genitourinary
• CNS
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 Anticipated severe or prolonged


severe neutropenia neutropenia
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

LOW RISK Complex infection


Low Risk Treatment
• Low risk • Vigilant observation
• No focus of infection, hemodynamically • Access to medical care 24-7
stable • Return to clinic if
• No systemic symptoms other than fever • Positive cultures
• No organ failure, pneumonia, soft tissue • Persistent/recurrent fever @ 3-5 days
infection • Unable to tolerate PO regimen
• Recovering bone marrow
• Cipro 500 mg PO Q8h + amoxicillin-
• Reliable patient
clavulanate 500 mg PO Q8h
MAINTAIN BROAD
SPECTRUM ACTIVITY FOR A
MINIMUM OF 7 DAYS OR
UNTIL ANC >500
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
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
Antifungals
• Easy to Initiate/ Difficult to stop
• Aggressive search for Fungal Infections
• Pulmonary Aspergillosis/Sinusitis / Hepatic Candidiasis
ANTI FUNGALS
• AMPHO B IV (1.5 mg/kg/day) drug of choice for
high risk patients
Alternative options
• FLUCONAZOLE (10 mg/kg/day)
• ITRACONAZOLE (3-5 mg/kg)
• ECHINOCANDINS
• Voriconazole is NOT FDA approved for empiric
therapy for persistent fevers in FN
Fluconazole ~ candida
DO NOT Use
• Fluconazole acceptable if NO Fluconazole if:
Moulds and Resistant Candida • Evidence of Sinusitis
( C. Krusei and C. glabrata ) or
Uncommon. • Radiographic
evidence of Evidence
of Pulmonary disease
Low risk patients
• If patient has received
Fluconazole
prophylaxis before.
Antibiotic Prophylaxis for 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&1094,2005
NEJM 353:977,988&1052,2005
Use of Antiviral Drugs

• Antiviral drugs are not recommended for routine


use unless clinical or laboratory evidence of viral
infection is evident.
• Granulocyte Transfusions
Granulocyte transfusions are not recommended
for routine use.

• Use of Colony-Stimulating Factors


Use of colony-stimulating factors is not
routine but should be
considered in certain cases with predicted
worsening of course.
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
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