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Neutropenic Fever: Dr. Meral Sönmezoğlu
Neutropenic Fever: Dr. Meral Sönmezoğlu
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Definition
• Febrile Neutropenia
• • Fever
• A single oral Temp > 38.3ºC or ³ 38.0ºC over at
least one hour
• • Neutropenia
• Neutrophil count < 500/mm3 or < 1,000/mm3 with
a predicted decline to £ 500/mm3
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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
Key Points
• 50% to 60% neutropenic have documented
infection
• • Bacteremia noted in ¼ with ANC <100
• • Signs & symptoms are subtle
• • More gram-negative organisms
• • Neutrophil recovery determines treatment
• • Typically 2 to 7 days to respond to antimicrobial
therapy
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Neutrophil?
• Most common white blood cell
—Filled sacs of lysosomes
—Produced in bone marrow
—Half-life approximately 8 hours
—60 billion produced each day
—Age & race varies production
—Production slower in elderly
—Slightly lower counts in African
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Role of Neutrophils
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Absolute Neutrophil Count
(ANC)
• Is derived by multiplying the WBC count times the
percentage of neutrophils in the differential WBC
count.
• The percent of neutrophils consists of the
segmented (fully mature) neutrophils) + the bands
(almost mature neutrophils)
• ANC = WBC x (% neutrophils + bands)
• The normal range for the ANC = 1.5 to 8.0 (1,500 to
8,000/mm3)
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ANC Risks
• ANC predicts risk for serious (fatal) infections
• • ANC < 1000/mm3 increases risk of infection
• • ANC < 500/mm3 dramatically increases risk
• • Risk, frequency and severity of infection related
to
• – Degree or depth of neutropenia
• – Duration of neutropenia
• – Rate at which neutropenia occurs
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Neutropenia is defined as…
• ANC < 500 cells/mm3 or
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Neutropenia
• • Abnormally low proportion of neutrophils
• • Viral infection, chemotherapy and radiotherapy
• • Lowers immunologic barrier to infections
• • Mild neutropenia – ANC falls below 1500/mm3, not >
1000
• • Moderate neutropenia – ANC falls between 500
-1000/mm3
• • Severe or profound neutropenia – ANC falls below
500/mm3
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Types of Neutropenia
• • Severe chronic
• • Cyclic
• • Congenital
• • Chronic idiopathic
• • Acquired nonmalignant
• • Chemotherapy/radiation induced
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Causes of Neutropenia
• Diseases decreasing production of Neutrophils
• – Leukemia, aplastic anemia & myelofibrosis
• – Infections such as virus, tuberculosis & typhoid
• – Abnormalities of bone marrow
• • Destruction or damage of Neutrophils
• – Drug toxicities & vitamin deficiencies
• – Drugs stimulating immune system to attack cells
• – Autoimmune disorders (SLE, RA)
• – Radiation therapy
• – Severe infections
• • Pooling of neutrophils
• – Overwhelming infections
• – Heart-lung bypass & hemodialysis
• • Hypersplenism
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Complications
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Neutropenia Complications - Fever
• Temperature is the cardinal symptom
• Often the only sign of infection
• Assess 4 x day or ↑ if symptomatic
• Severely neutropenic – often no fever
• Subnormal temperature – severe sepsis
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NCI defines Febrile Neutropenia as…
• A condition marked by fever and a lower-than-normal
number of neutrophils in the blood.
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Facts on Febrile Neutropenia
• First identified chemo-induced FN in 1970s,
mortality rate was >50%
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Clinical Consequences
• • Clinical
• – ↑ risk life threatening infection → death
• – Dose-limiting toxicity of chemotherapy
• – Compromised treatment effectiveness
• – Dose delays and reductions
• – Long-term survival reduced
• • Quality of Life
• – ↑ in anxiety and fatigue
• • Economic
• – Significant ↑ in direct & indirect costs
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Pathogenesis
• • Normal immune response
• • T & B cells are produced
• • Foreign proteins recognized
• • Neutrophils primary phagocytic responder
• • Neutropenia decreased circulating leukocytes
• • T-lymphocyte function is suppressed
• • Reduced ability to recognize foreign tissue,
atypical microbes & viruses
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the normal action of neutrophils 20
Predisposing Factors
• Treatment Related
• • Previous history
• • Chemotherapy regimen
• – Anthracyclines
• – Dose-dense regimens
• – Planned relative dose intensity >80%
• • Preexisting neutropenia
• • Extensive prior chemotherapy
• • Concurrent/prior radiotherapy to marrow-containing bone
• • Concurrent use of antibiotics, antifungals, sulfas,
• allopurinol and/or corticosteroids
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Predisposing Factors
• Patient-Related
• • Age >65 & female
• • Degeneration of immune function
• • Poor performance & nutritional status
• • Open wounds or active tissue infection
• Cancer-Related
• • Bone marrow involvement with tumor
• • Elevated lactic dehydrogenase
• • Advanced or uncontrolled cancer
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Predisposing Factors
• Comorbidities
• • COPD
• • Cardiovascular disease
• • Hepatic disease ( bili & alk phos)
• • Renal insufficiency (creat. < 30 mL/min)
• • Diabetes mellitus
• • Low baseline hemoglobin
• • Active tissue infection
• • Mucositis
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Examination of Neutropenic Patient
• Look for a source of the sepsis
• – General examination
• – Ear, mouth, and nose examination
• – Fundoscopy
• – Gastrointestinal tract
• – Respiratory system
• – Genitourinary tract
• – Cardiovascular system
• – Neurological – eg, neck stiffness
• Remember immunosuppressed patients may not mount clinical
signs
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Common Infection Sites
• • Mucosal damage
• • Primary anatomic sites of infection
• • Skin damage – invasive procedures
• • Bloodstream (15% – 20%)
• • GI tract (enterocolitis & perirectal)
• • Integument (skin, vascular access sites)
• • Respiratory (sinusitis & pneumonia)
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Evaluation
• Clinical Features
• • Minimal or absent signs of infection
• • Lack of inflammatory response
• • No erythema, induration or purulence
• • Mental status changes
• • Restlessness and fatigue
• • Diagnostic findings
• – Low albumin level (<3.5 mg/dL)
• – Elevated LDH
• – Elevated Alkaline phosphatase
• – Hyperglycemia
• – Elevated bilirubin
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Risk Assessment
• • Two classification systems
• – MASCC
• – Talcott
• • Low Risk
• – Presents with fever only
• – No focus of bacterial infections
• – No chills or hypotension
• – Treatment - oral antibiotics/outpatient
• • High Risk
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Diagnostic Testing
• • Complete blood count
• • Bone marrow biopsy
• • Immunologic testing
• • Liver function tests
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Diagnostic Testing
• • CBC, D-dimers and fibrinogen
• • Liver function tests
• • Coagulation screen
• • Chest X-ray
• • Blood cultures
• • Urine dipstick, C & S and cytology
• • Stool C & S, OCP, Clostridium difficile toxin
• • Skin lesions for culture
• • Bronchoscopy and CT scans
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Diagnostic Testing…
• Cultures
• Practice Guidelines in Oncology – v. 1.2008
• • Collect during or immediately after spike
• • Two blood samples obtained
• – 1 peripheral & 1 central
• – 2 peripheral or 2 central
• • If indicated, consider
• – nose, oropharynx, urine, stool & rectum
• – vascular access site
• – new or undiagnosed skin lesions
• • If symptomatic, sputum culture followed by x-ray
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Common Bacterial Pathogens
Associated with FN
• Gram-positive Organisms • Gram-negative Organisms
• – Staphylococcal species • – Escherichia coli
• • Coagulase-negative • – Klebsiella species
• staphylococci • – Pseudomonas aeruginosa
• • Staphylococcus aureus
• – Enterobacter species
• – Streptococcal species
• – Acinetobacter species
• • Streptococcus
• – Non-aeruginosa
• pneumoniae
• • Streptococcus
• Pseudomonas species
• pyogenes
• – Enterococcal species
• – Corynebacterium species
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Infection Control
• Educate the patient and family
• – Avoid exposure to risks
• – Control environment risks
• – Avoid invasive procedures
• – Implement measures to lessen severity or
longevity
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Treatment Prophylaxis
Granulocyte-colony stimulating factor
• G-CSF is a growth factor
• Stimulates the bone marrow
• Prophylactic use, eg, following chemotherapy
• Counteract the infection along with antibiotics
• Shortens neutrophil count to recover
• Reserved for high risk neutropenia or recurrent infections
• Evidence does not show any clear benefit for the use of G-CSF
• Side effects include pain and itchiness at the site of injection
• Can itself cause fever, diarrhea and vomiting
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Antibiotics –
Broad Spectrum Beta-Lactam
Once cultures collected, begin the following (if no PCN
allergy)
• Cefepime (MAXIPIME) 2 gms IV q 8 hr x 7 days or until
neutrophil recovery
OR
• Imipenem-cilastatin (PRIMAXIN) 500 mg IVPB over 60 min
q 6hrs x 48 hours
OR
• Piperacillin + Tazobactam (ZOSYN) 3.375 gm IV q 6 hrs x 7
– 10 days
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Antibiotics
• You may also add
• ** Add Vancomycin 1 gm IV q 12hr x 48 hours
(for combination therapy only)
** Clinical Indications for Empiric Vancomycin Therapy
1. Clinically apparent, serious catheter-related infection
2. AML, ALL or NHL
3. Hypotension or septic shock without an identified pathogen
4. Known colonization or past history of MRSA, MRSE, or strep viridians
5. Mucositis (min stage 2) present along with fever
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Significance of Febrile Neutropenia?
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Initial Work-Up of Patients with Fever
And Neutropenia
• Comprehensive history
• • Physical examination (inability to mount an adequate
inflammatory response)
• • Diagnostic work-up:
• – CBC
• – Cultures of blood, urine, sputum, wounds, skin lesions
etc.
• – CXR
• – Others
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Presentations of Infection
• Lack of signs and symptoms
• Rapid progression of infection
• Unusual sites of involvement
• Unusual infecting organisms
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Risks for FN Episodes
• Low-risk pts
• – short-lived neutropenia
• – outpt with no comorbidities
• – access to medical and family assistance
• • High-risk pts
• – prolonged neutropenia
• – uncontrolled cancer
• – comorbidities
• – hematologic malignancies or SCT
• – in the hospital
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Scoring Index For Identification of
Low Risk Pts
• Extent of illness Score
• – No Sxs 5
• – Mild Sxs 5
• – Moderate sxs 3
• • No hypotension 5
• • No COPD 4
• • Solid tumor or no fungal infection 4
• • No dehydration 3
• • Outpt at onset of fever 3
• • Age < 60 y 2
• Risk index >21 ® low risk pt
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What Therapy?
Low Risk
—IV combination
—IV Monotherapy
—Oral either inpatient or ??outpatient
—Short admission (24 hrs.) then D/C
High Risk – must be hospitalized
—IV combination or IV monotherapy
—Consider G-CSF
Rx Options for FN
• • Low-risk pts considered for oral in/outpt therapy:
• – FQ ± amox/clav
• • High-risk pts hospitalized for IV AB therapy
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Selection of Initial Ab Regimen
• Bacterial isolates recovered from other pts at the same
• hospital
• – Type
• – Frequency of occurrence
• – Antibiotic susceptibility
• • Special circumstances (drug allergy, organ disfunction)
• • Inpt or outpt management
• • Future epidemiology depends on the policy in the use
• of antimicrobial agents!!!!
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Evidence-Based Evaluation of Important
Aspects of Empirical Ab Rx in FN
• No benefit from + of AG to the initial Rx (significantly rate of AE,
• especially nephrotoxicity)
• • No need for empirical + of glycopeptide after 3-4 d of fever
• – In clinically stable pts without resistant or skin/soft tissue
• infections, glycopeptide can be delayed for another 3-4 d
• • The choice of drugs for monotherapy
• – Ceftazidime associated with significantly ¯ response rate vs.
• other Ab (cefepime, pip/tazo, carbapenems)
• • Choice of drug as standard first-line Rx should depend on drug
• costs, local resistance and potential for resistance induction
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• Bronchoscopy with BAL
• revealed Pneumocystis
jirovecci
• pneumonia
• • He was Rx with TMP/SMX
and
• did well
• • Unusual radiographic
findings
• of PCP pneumonia
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Evidence-Based Evaluation of Important
Aspects of Empirical Ab Rx in FN
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Other Causes of Persistent Fever
• C difficile colitis
• • Catheter-associated infections
• • Drug fever
• • Graft-versus-host disease
• • Hematomas
• • Pulmonary emboli
• • Splenic infarct
• • TB
• • Underlying disease
• • Adrenal insufficiency
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Combination IV Therapy
• Combined therapy with at least one drug which
covers pseudomonas
—KGH - Cefotaxime & Gentamicin
—Other options: Piperacillin/ aminoglycoside
—Avoid aminoglycosides in those on Cisplatin or
other renal toxic agents
Immediate Vancomycin?
hypotension
Monotherapy
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Procoagulant Response in Sepsis
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