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Dr. Meral SÖNMEZOĞLU

Yeditepe University Hospital

Neutropenic Fever(Febril neutropenia)

1. Know the general terminology

2. Learn clinical significances and main organisms

3. Know predisposing factors

4. Explain the risk assessment (scorring) system

5. Understand the management strategies and prevention

Learning objects

Definition

• Febrile Neutropenia is a medical emergency and must be dealt with immediately.

• Any temperature over 100.1 F (Fahrenheit) or 37.3 C (Celsius) should be reported to the medical oncologist without delay.

• Hours and minutes are critical.

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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

Significance of Febrile Neutropenia?

• Infections in the neutropenic patient can be rapidly fatal if not managed properly

—Mortality rate in the 1960’s was 50%

—With proper management 5% today

Facts on Febrile Neutropenia

• First identified chemo-induced FN in 1970s, mortality rate was >50%

• Currently mortality rate<5% with proper identification and management

• Only 30-50% of patients have identified sources of infection

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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

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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

Fever

• Fever epidemiology and etiology • Solid tm – FEN %10-50• Hematological malignity – FEN >%80• Fever• -20-30% Clinically documented infection• -10-25% Bacteremia• -45-70% Unexplained

Freifeld AG et al. Clin Infect Dis 2011

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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

• primary defense against bacterial infections

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12the normal action of neutrophils

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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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

• ANC <1,000 cells/mm3 with a predicted decline to <500 cells/mm3

—over the next 48 hours

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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

• Febrile neutropenia is a potentially life-threatening complication of myleosuppressive

chemotherapy

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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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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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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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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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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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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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The Multinational Association for Supportive Care in Cancer Risk-Index Score

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Characteristic Weight

Burden of febrile neutropenia with no or mild symptomsa

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No hypotension (systolic blood pressure .90 mmHg) 5

No chronic obstructive pulmonary diseaseb 4

Solid tumor or hematologic malignancy with no previous fungal infectionc

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No dehydration requiring parenteral fluids 3

Burden of febrile neutropenia with moderate symptomsa

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Outpatient status 3

Age ,60 years 2

Clinical Practice Guideline CID 2011:52 (15 February)

Presentations of Infection

• Lack of signs and symptoms• Rapid progression of infection• Unusual sites of involvement• Unusual infecting organisms

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Initial Work-Up of Patients with FeverAnd 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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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 in Neutropenic Patients

Common gram-positive pathogens• Coagulase-negative staphylococci

• Staphylococcus aureus, including methicillin-resistant strains

• Enterococcus species, including vancomycin-resistant strains

• Viridans group streptococci• Streptococcus pneumoniae• Streptococcus pyogenes

Common gram-negative pathogens• Escherichia coli• Klebsiella species• Enterobacter species• Pseudomonas aeruginosa• Citrobacter species• Acinetobacter species• Stenotrophomonas maltophilia

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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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Principles of Management of FN

• Risk of documented infection is related to the degree and duration of neutropenia• Recovery of neutrophil count is critical in response

to Rx• Classic signs and symptoms may be absent• Untreated infection may disseminate widely• Broad spectrum antibiotics must be instituted

promptly

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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

Treatment ProphylaxisGranulocyte-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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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

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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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 (TIENAM) 500 mg IVPB over 60 min q

6hrs x 48 hours

OR• Piperacillin + Tazobactam (TAZOCIN) 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

• For patients exhibiting signs of sepsis (according to the SIRS Criteria)• Gentamicin 5mg/kg IV x one dose• ( 3 mg/kg if SCr ≥ 1.5 or ≥ 70 years o

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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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Outpatient therapy

• Not considered the standard but is often done• Must be reliable patient who doesn’t live alone,

able to take oral antibiotics• Re-evaluate q 2days until ANC > 0.5 x 109/L and

afebrile x 48hrs.• If complications or continued fever admit

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Neutropenia without fever

• If patient is ill and neutropenic, but doesn’t have fever still treat with same regimens • Beware in the elderly – might not mount a fever• afebrile pt. with neutropenia and severe diarrhea –

Ciprofloxacin recommended

Neutropenia without fever

• If patient is ill and neutropenic, but doesn’t have fever still treat with same regimens • Beware in the elderly – might not mount a fever• afebrile pt. with neutropenia and severe diarrhea –

Ciprofloxacin recommended

QUESTIONS

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