1

Dr. Meral SÖNMEZOĞLU

Yeditepe University Hospital

Neutropenic Fever

• 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.

2

3

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

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

5

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

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

6

Role of Neutrophils

• primary defense against bacterial infections

7

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)

8

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

9

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

10

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

11

Types of Neutropenia

• • Severe chronic• • Cyclic• • Congenital• • Chronic idiopathic• • Acquired nonmalignant• • Chemotherapy/radiation induced

12

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

13

Complications

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

chemotherapy

14

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

15

NCI defines Febrile Neutropenia as…

• A condition marked by fever and a lower-than-normal number of neutrophils in the blood.

• A single oral temperature of >38 .3 ْ C

• or a temperature of >38 C measured twice over a 1-hour period in a patient with neutropenia of <1,000 cells/mm3 with a predicted decline to <500 cells/mm3 over the next 48 hours

16

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

17

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

18

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

19

20the normal action of neutrophils

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

21

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

22

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

23

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

24

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)

25

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

26

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

27

Diagnostic Testing

• • Complete blood count• • Bone marrow biopsy• • Immunologic testing• • Liver function tests

28

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

29

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

30

Common Bacterial PathogensAssociated with FN

• Gram-positive Organisms• – Staphylococcal species• • Coagulase-negative• staphylococci• • Staphylococcus aureus• – Streptococcal species• • Streptococcus• pneumoniae• • Streptococcus• pyogenes• – Enterococcal species• – Corynebacterium species

• Gram-negative Organisms• – Escherichia coli• – Klebsiella species• – Pseudomonas aeruginosa• – Enterobacter species• – Acinetobacter species• – Non-aeruginosa• Pseudomonas species

31

Infection Control

• Educate the patient and family• – Avoid exposure to risks• – Control environment risks• – Avoid invasive procedures• – Implement measures to lessen severity or

longevity

32

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

33

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

34

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

35

36

37

38

39

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

Significance of Febrile Neutropenia

• Most patients don’t have bacterial infection—30-50% will have infection

—Primary sites: GI tract – Skin

—Risk increases with lower counts (< 0.5 vs. < 0.1) and duration of neutropenia

Significance of Febrile Neutropenia

—But no reliable way of knowing or predicting who is infected

—So all are treated with empiric antibiotics

—Fevers may be due to other infections or to non-infectious causes

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

43

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

44

Presentations of Infection

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

45

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

46

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

47

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

49

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!!!!

50

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

Glasmacher A . Clin Microbiol Infect 2005;11

51

• Bronchoscopy with BAL• revealed Pneumocystis

jirovecci• pneumonia• • He was Rx with

TMP/SMX and• did well• • Unusual radiographic

findings• of PCP pneumonia

52

Evidence-Based Evaluation of Important Aspects of Empirical Ab Rx in FN

53

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

54

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?

• Generally not recommended- add in on basis of cultures• Recommended for the these situations:

Suspected serious catheter infections Known colonization with organisms

resistant to other antibiotics +ve blood cultures hypotension

Monotherapy

• RCT have shown equivalence:

—Ceftazadime

—Impenem/Cilastatin

—Meropenem

Oral Therapy

NEJM July 1999• Two randomized trials looked at oral vs. IV

inpatient therapy in low risk patients• N= 112 NCI N=356 European• Slightly different definitions of the low risk group

Oral Therapy

• Both showed that oral therapy with Ciprofloxacin and amoxicillin-clavulanate was equivalent to IV therapy• Success rates -- oral vs. IV

—71 vs. 67% / 80 vs. 77%

• No deaths NIH trial• No differences in the deaths European trial

Duration of Therapy

1. If ANC 0.5 for two days+ Afebrile X 48 hrs.+ No infection

2. If continued neutropenia continue to 5-7 days of afebrile then D/C

3. If on IV can be switched to oral medication as directed by cultures or Ciprofloxacin/Clavulin and potentially discharge if stable

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

Outpatient Therapy

• Can we translate this to the outpatient setting?—Possibly

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

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

68

Russell J. N Engl J Med 2006;355:1699-1713

Inflammatory Responses to Sepsis

69

Russell J. N Engl J Med 2006;355:1699-1713

Procoagulant Response in Sepsis