FEBRILE NEUTROPENIA
WHERE DO WE STAND?
Dr. / Khaled Abulkhair, PhD
Medical Oncology SCE, Royal College
Assistant Professor of clinical Oncology
Mansoura University
• Gary H. Lyman and Kenneth V. I. Rolston: How We Treat
Febrile Neutropenia in Patients Receiving Cancer
Chemotherapy. jop.ascopubs.org , May, 2010.
• Management of febrile neutropenia: ESMO Clinical
Practice Guidelines, Annals of Oncology 21 (Supplement
5): v252–v256, 2013
• NCCN guidelines, supportive care, infection in cancer
patients, 2014.
• Guidelines for the Management of Febrile Neutropenia in
Oncology Patients, Nottingham Antibiotic Guidelines
Committee,
http://nuhnet/diagnostics_clinical_support
/antibiotics , Dec 2009
• IDSA guidelines 2010
WHAT IS YOUR JOB?
If your patient is a 65 y.o known metastatic NSCLC with
the following co-morbidities; COPD, hypertensive, and
cirrhotic liver with maintained LFT presented post his
first cycle of Docetaxel + Carboplatin with severe oral
mucositis and fever. CBC showed Neutropenia.
- What would be his risk dying of his infection?
 Fever in the setting of neutropenia is considered a medical
emergency
requiring
immediate
evaluation
and
administration of empiric broad-spectrum antibiotics.1
 Early studies demonstrated that patients with febrile
neutropenia not promptly treated often experience a rapidly
fatal outcome, most notably because of Gram negative
bacteremia.2
 Recent studies of unselected patients with cancer with
febrile neutropenia have reported rates of mortality of 5%
to 20%, increasing in direct proportion to the number of
major infectious complications and comorbid medical
conditions (Fig 1)3.
SIMPLE MESSAGES
Always remember infection can kill.
Febrile Neutropenia is a medical
Emergency.
Be prepared and updated.
How to improve our practice?
NEUTROPENIA
 Can vary depending on institution:
• Usually defined as absolute neutrophil count (ANC)
<1000-1500 cells/microliter…How to Calculate
• ANC = WBC (cells/microliter) x %(PMNs + bands) /100
 Further categorized as:
• Severe (ANC <500)
• Moderate (ANC between 500-1000), variable
hospitalization requirement
• Mild (ANC 1000-1500), which can typically be managed
as OPD
• F.N is defined as Fever 38.30 or 380 over 1 h with
ANC of 500 /mm3 or less or a count of less than
1000/mm3 with expected drop to below 500/mm3 in
the next 48 hours.
• Remember:
• Neutropenic patient can present w/o fever despite infection
especially in elderly patients, those on steroids, and or
paracetamol.
• Deal with patients on chemotherapy who are critically ill,
hypotensive, tachcardiac or desaturated as being F.N untill
proven otherwise.
• Risk of infection and severity of infection related to ANC
level and duration of neutropenia.
• Neutropenia can occur via 4 mechanisms:
• Decreased production
• Ineffective granulopoiesis
• Shift of circulating PMNS to vascular
endothelium or tissue pools
• Enhanced peripheral destruction
• 2 Categories
• Acquired
• Congenital
• 2 Categories
• Acquired
• Congenital
• Acquired:
• Most common is post infectious (bacterial, viral,
parasitic, rickettsial)
• 2nd most common is drug induced:
• Drugs with highest risk: clozapine, antithyroid
drugs, antidiabetics, chloramphenicol, cytotoxics
(post chemo….), bactrim and sulfasalazine.
• Hypersplenism
• Bone marrow disorders (aplastic anemia, leukemias,
myelodysplasia, neutropenia is not isolated defect in
cases like these)
INITIAL ASSESSMENT
Guidelines are not a substitute for a good clinical judgment.
• First and most imp…..listen to your patient:
 Do not forget to ask about any CNS manifestations.
• Thorough physical examination:
 Vital signs including pain…
 What is meant by hemodynamic instability?
 Pay attention for VAD
 Perianal inspection: avoiding digital exams or rectal temps
INVESTIGATIONS
• Investigations should include:
 CBC diff, Basic chemistries, Cultures from all potential
sites, along with two sets of blood cultures from peripheral
veins or one set each from a peripheral vein and a central
VAD.
 Do not discard the first few cm of blood from VAD
 Chest radiographs.
o Other investigations are guided by the clinical situation.
o Although a specific organism will not be found in more than
half of patients with F.N, a presumptive diagnosis of infection is
important.
o (DTTP), which is the difference in time between
positivity of results between catheter culture and
peripheral blood culture. A DTTP of ‡2 h is a highly
sensitive and specific indicator of catheter-related
bacteremia.
o All cases of catheter-related infection (CRI) in the
setting of FN require decision making on the choice
and duration of i.v. antibiotics, and the need for
catheter removal.
o When CRI is suspected, and the patient is stable, the
catheter
should
not
be
removed
without
microbiological evidence of infection [ESMO,2010].
THE UGLY TRUTH
 Patient presented to his assigned clinic, he cannot come in a
different day?
 Lucky if someone noticed he is febrile and needs admission!
 Few hours passed till he is admitted. No Antibiotics till next day.
 At 7-8 PM, the Resident call the senior staff asking what to do ?
 Do cultures? Give antibiotics? Send to ICU?
IF YOU ARE AN ONCOLOGIST....DO NO HARM
 Urgent assessment…any time any day is needed
 Urgent Admission
 Urgent treatment within 30-60 mint of
presentation!
 Urgent ICU referral if needed
• Currently, Gram-positive organisms are the
predominant bacterial pathogens in this setting,
with
coagulase-negative
staphylococci,
Staphylococcus aureus, Enterococcus spp., and
viridans group streptococci being isolated most
often.4
• Among Gram-negative bacilli, Escherichia coli,
Klebsiella spp., and Pseudomonas aeruginosa
remain the predominant species, although other
Enterobacteriaceae,
Stenotrophomonas
maltophilia, and Acinetobacter spp. are isolated
frequently.5
o Approximately 10% to 15% of bacteremias are
polymicrobial, with Gram-negative bacilli being
isolated from more than 80% of these infections.6
o Resistance to Antimicrobials
o Of particular concern, more than 50% of
Staphylococcus aureus isolates are MRSA, and
vancomycin resistance among enterococci constitutes
nearly 30% of enterococcal isolates.
o Local epidemiological bacterial isolates and resistance
patterns are crucially important in determining firstchoice empirical therapy, since coverage for MRSA or
resistant Gram-negative bacteria may be required
(ESMO,2010).
MANAGEMENT
 Best way to treat F.N is to prevent its occurrence.
 Prophylaxis is a big subject with many controversies will be
discussed in another session.
 Empiric, broad-spectrum antibiotic therapy should be
administered promptly to all patients with febrile neutropenia. 9
 Patients’ risk should be quickly assessed to determine …mono
or combinations, hospital or home.
 Low-risk patients may be defined as ambulatory patients with
good performance status and no serious comorbidity and
anticipated short duration of severe neutropenia or those with
an index score of 21 or more.11
RISK STATUS ASSESSMENT
Is my patient in need for Vancomycin?
Catheter-related infection/Port tunnel infection/cellulitis
 Gram-positive organisms on blood culture
 Hypotension
 Mucosal damage e.g. (CCRT)
 Colonization with penicillin-resistant pneumococci or methicillinresistant Staphylococcus aureus.
Should I start G-CSF?
G-CSF should not be used routinely in the treatment of established
febrile neutropenia, although they may be considered in patients at
increased risk for serious complications including mortality, ANC ≤
100, and or age ≥ 65 with comorbidities.
G-CSF use is discouraged in afebrile neutropenia!
Should I call ICU?
CONTINUATION OF ANTIBIOTIC TREATMENT
SPECIAL SITUATIONS
SIMPLE MEASURES AND ONGOING CARE
• Monitor CBC diff and biochemical profile daily.
• Assess intravenous sites daily for any signs of infection.
• Assess the oral cavity status every 12 hours.
• Assess the skin daily for breakdown, lesions, rashes etc.
• Assess any wounds for signs of infection.
• Assess for any change in urinary function including dysuria
frequency, and hematuria.
• Assess for any changes in bowel habit.
• Assess female patients for vaginal candidiasis.
• Assess patients for any signs of peri-anal infection.
SIMPLE MEASURES AND ONGOING CARE
• Patients will be cared for in an environment that minimizes
the risk of infection from other patients, staff and visitors.
• Protected isolation must be clearly indicated as per the
policy.
• Educate the patient and relatives about the need to restrict
visitors with transmissible illnesses Or recently vaccinated
with live vaccines.
• Careful hand washing is the single most important action for
the health professional, patient, the patient’s family and
visitors, in preventing cross infection.
• Fresh flowers, plants should not be placed in the patient’s
room.
• Denture mugs and soap dishes should also be
removed.
• Food may be a source of infection and dietary
restrictions may be necessary.
• Sanitary towels should be used instead of tampons.
• Ensure patients are encouraged/assisted to shower
daily.
• The rooms should be cleaned daily and all surfaces
damp dusted.
LIST OF DONOT DO
 Do not underestimate F.N; it can kill.
 Do not take too much time to give first dose of Antibiotics.
 Do not wait for Lab results…. Use your clinical judgement.
 Do not do PR examination.
 Do not forget… you are caring for a whole patient not only F.N.
 Do not hesitate calling for help from ICU if needed.
 Do not stop treatment early…relapse of not-fully treated
infections is dangerous.
 Do not forget to adjust doses of chemotherapy for the
subsequent cycles and or Renal/Liver impairment.
THE FUTURE….I HOPE WILL NOT BE UGLY
• Post chemotherapy Note Card.
• Emergency admission any day anytime.
• Resident: “Hello Dr/Khaled. Mr/Ahmed has a temp of 39C,
neutrophils are 0.1. He is quite well, BP 140/70, pulse 100, and
sats 95%. I have taken cultures, and I have given first doses of
antibiotics”, Do you have anything more to add?
REFERENCES
•
1- Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial
agents in neutropenic patients with cancer. Clin Infect Dis 34:730-751, 2002
•
2- Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationships between circulating
leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328-340, 1966.
•
3- Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity, and cost associatedbwith
febrile neutropenia in adult cancer patients. Cancer 106:2258-2266, 2006.
•
4- Yadegarynia D, Tarrand J, Raad I, et al: Current spectrum of bacterial infections in patients
with cancer. Clin Infect Dis 37:1144-1145, 2003.
•
5- Safdar A, Rolston KV: Immunocompromised hosts: Stenotrophomonas maltophilia—
Changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis
45:1602-1609, 2007.
•
6- Rolston KV, Bodey GP, Safdar A: Polymicrobial infection in patients with cancer: An
underappreciated and underreported entity. Clin Infect Dis 45:228- 233, 2007.
7- Klastersky J, Ameye L, Maertens J, et al: Bacteraemia in febrile neutropenic cancer patients.
Int J Antimicrob Agents 30:S51-S59, 2007 (suppl 1).
8- Rolston KV: Challenges in the treatment of infections caused by gram positive and gram negative bacteria in patients with cancer and neutropenia. Clin Infect Dis 40:S246-S252,
2005 (suppl 4).
9- Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents
in neutropenic patients with cancer. Clin Infect Dis 34:730- 751, 2002.
10- Kern WV: Risk assessment and treatment of low-risk patients with febrile neutropenia. Clin
Infect Dis 42:533-540, 2006.
11- Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for
Supportive Care in Cancer risk index: A multinational scoring system for identifying low -risk
febrile neutropenic cancer patients. J Clin Oncol 18:3038-3051, 2000.
12- Rolston KVI, Frisbee-Hume SE, Patel S, et al: Oral moxifloxacin for outpatient treatment of
low-risk, febrile neutropenic patients. Support Care Cancer 18:89-94, 2010.
13- Klastersky J, Paesmans M, Georgala A, et al: Outpatient oral antibiotics for febrile
neutropenic cancer patients using a score predictive for complications. J Clin Oncol 24:41294134, 2006