FEBRILE NEUTROPENIA

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FEBRILE NEUTROPENIA

• Saima Abbas M.D
• Infectious Diseases
• Fellow-PGY5

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Why is this an Oncologic emergency ??
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Infection ABX Immune system cure

• Normal Gross Anatomy
• Skin Integrity
• Intact mucous membranes
• Intact ciliary function
• Absence of Foreign Bodies

• Innate Immunity
• ( PMN,
• Macrophages, NK cells, Mast cells and basophils)
• Complement
• Adaptive immunity
• T cells CD 4 and CD 8
• B cells

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Case 1July 10th 2009 - NF 1

• You are paged at 500am by the nurse taking care
  of Mr. Thomas on 4 AB
• He spiked a fever of 38? C (100.4?F) one hour
  ago.
• -There is no order for Tylenol.

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• You check your Hem Oncology List .
• Per sign out
• The patient was recently diagnosed with AML is
  S/P chemotherapy and is stable.
• You can
• Order Tylenol and take the next page.
• OR..

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OR
Am I missing febrile Neutropenia???

• If you are alert, you think

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What are the facts you need to know?

• Does 38 ? C define febrile neutropenia?
• Whats his Absolute Neutrophil Count?
• Any transfusion in the last 6 hours?

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Definition of Fever in FN

• A single oral temp ? 38.3 ? C
• (101 ? F)
• or
• A temperature of ? 38 ? C
• (100.4 F) on two occasions separated by 1 hour

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• You request her to repeat the temperature and she
  reports 38. 2? C (100.8 ?F)

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Dont be tricked

• If temperature 37 ? 38? C , repeat temperature in
  1 hour to see if the above criteria for treatment
  are met
• Clinical signs of septicemia
• Good history of fever detected by patient
  before admission and afebrile when you evaluate
  the patient.

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Definition of Neutropenia

• ANC ? 500/mm3 or
• ? 1000/mm3 and predicted
• decline to ? 500/mm
• Clin Inf Dis, 200234730-51

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ANC Mr. Thomas

• WBC 0.7
• Segs 38
• Bands 2

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Absolute Neutrophil Count

• (Total of WBC) x ( of Neutrophils) ANC
• Take the percent of neutrophils (may also be
  polys or segs) percent bands
• Convert percent to a decimal by dividing by 100
  (Example 40 40/100 0.40) (move the decimal
  2 points to the left)
• Multiply this number by the total White Blood
  Cells (WBC)

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0.7 X 1000 70040 40/1000.40 700 X 0.40
280

• Calculation

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Neutropenia

• Normal ANC 1500 to 8000 cells/mm³
• Neutropenia ANC lt 1500 cells / mm3
• Mild Neutropenia 1000-1500 cells / mm3
• Moderate Neutropenia 500-999 cells / mm3
• Severe Neutropenia lt 500 cells / mm3
• Profound Neutropenia lt100 cells/ 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

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Risk of Infection as Absolute Neutrophil Count
Declines
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Epidemiology

• Up to 60 febrile neutropenia episodes
  infection (microbiological or clinical)
• 20 patients with ANC lt100 cells/mm³ with
  febrile neutropenia episodes have bacteremias.

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Epidemiology --NEJM, 19712841061

• Retrospective data have shown that
• 50 of Pseudomonas Aeruginosa Bacteremia
  result in death within 72 hours when ANC is lt
  1000
• Early trials aimed at Pseudomonas showed that
  Carbapenicillin /Gentamicin decreased Mortality
  by 33
• Journal of
  Infectious diseases, 197814714

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Epidemiology
Viscoli et al, Clin Inf Dis40S240-5

• Changing etiology of bacteremia
• IATG-EORTC 1973-2000 trials of febrile
  neutropenia

• Gram positive dominant since mid 1980s
• 1) More intensive chemoTx
• Mucositis
• 2) In-dwelling catheters
• Cutaneous-IV portal
• 3) Selective antiBx pressure
• Fluoroquinolones
• Co-trimoxazole
• 4) Antacids
• Promote oro-oesophageal colonisation with GPC

Gram negative resurgence
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Duration of Neutropenia

• lt 7 days LOW risk
• 7 to 14 days INTERMEDIATE RISK
• gt 14 days HIGH RISK

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Duration Of Neutropenia
1988,Rubin and colleagues

• lt 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 ( lt.001)
• patients with intermediate durations of
  neutropenia between 7 and
• 14 days had response rates of 79

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Common Microbes

• Gram-negative
• bacilli and cocci
• Escherichia coli
• Klebsiella species
• Pseudomonas aeruginosa
• FUNGI
• Candida- Non albicans emerging
• Aspergillus gtgt in HSCT

• Gram-positive cocci and bacilli
• Staph. aureus
• Staphylococcus epidermidis
• Enterococcus faecalis/faecium
• Corynebacterium species

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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

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THINK Strep. Pneumoniae Neisseria
meningitidis Hemophilus Influenzae

• Splenectomy

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Exam (be prepared to find no signs of
inflammation)

• HEENT Look in the mouth any oral sores
  periodontium, the pharynx
• Lungs
• Abdomen for tenderness- RLQ (signs of
  Typhilitis)
• Perineum including the anus -No rectal exam !

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Skin Exam- Ask the patient for any area of
tenderness?

• Skin
• Bone marrow aspirations sites,
• vascular catheter access sites
• and tissue around the nails
• Rashes (Drug eruptions/herpes zoster reactivation
  / Petechial rashes all are common in these
  patients)

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Febrile neutropeniaInvestigation

• Complete Blood Count (with Differential)
• -White cells, haemoglobin, platelets
• Biochemistry
• -Electrolytes, urea, creatinine, Liver function
• Microbiology
• -Blood cultures (peripheral and all central line
  lumens)
• -Oral ulcers or sores send swabs ( Viral Cx and
  fungal Cx )
• -Exit site swabs
• -Wound swabs
• -Urine Cultures (SSx/Foley Catheter) - pyuria ??
  UA
• -Stool Cultures and CDiff Toxin/PCR
• Radiology
• -Chest Xray /- CT abdomen/pelvis

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Lumbar puncture-

• Examination of CSF specimens is not recommended
  as a routine procedure but should be considered
  if a CNS
• infection is suspected and thrombocytopenia is
  absent or manageable.

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Skin lesions

• Aspiration or biopsy of skin lesions suspected of
  being infected should be
• performed for cytologic testing, Gram staining,
  and culture

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IMAGING in FN

• CXR if Symptomatic or if out pt Rx considered
• High resolution CT Chest Indicated ONLY if
  persistent fevers with pulmonary symptoms after
  initiation of empiric Abx
• CTA if suspect PE
• CT abdomen for Necrotizing Enterocolitis or
  Typhilitis
• CT brain R/o ICH / MRI of the spine or brain -
  more for evaluation of metastatic disease than FN

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Stratify risk of complications

• 1. Neutropenia
• ? with severity of neutropenia (lt 50/mm3)
• ? with duration of neutropenia (gt7 days)
• 2.Bacteremia
• Gram negative gt gram positive
• 3.Underlying malignancy and status
• Acute Leukemia
• Relapsed disease
• Solid malignancies Local effects eg obstruction,
  invasion
• 4.Co-morbidities, age gt60

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HIGH risk Patients

• Prolonged Neutropenia (gt14 days)
• Haematological malignancy/ Allogenic HSCT
• Myelosuppresive chemotherapy
• Concurrent chemotherapy and radiotherapy
• Age gt60
• Co-morbidities eg. Diabetes, poor nutritional
  status.
• Bone marrow involvement of cancer
• Delayed surgical healing or open wounds
• Significant mucositis
• Unstable (eg hypotensive, oliguric)
• On steroid dose gt20mg prednisone daily
• Recent hospitalization for infection

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a Concomitant condition of significance
(e.g.,shock, hypoxia, pneumonia, or other deep
organ infection, vomiting, or diarrhea).
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Risk model

• Model 2
• (Klatersky et al MASCC 2000 J Clin Onc)
• No or Mild symptoms 5
• Moderate symptoms 3
• No Hypotension 5
• No COPD 4
• Solid tumour / 4
• Haem malignancy
• (no fungal infection)
• Outpatient 3
• No dehydration 3
• Age lt60 yrs 2
• LOW RISKscoregt20

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ORAL vs IV

• For patients who are low risk for developing
  infection-related complications during the course
  of neutropenia,
• Oral ciprofloxacin plus amoxicillin/clavulana
  te
• Oral ciprofloxacin plus clindamycin
• for PCN allergy

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If inpatient and high risk

• EMPIRIC ANTIMICROBIAL THERAPY after Blood
  Cultures.Must be initiated within 1 hour

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THREE approaches for IV EMPIRIC therapy

• IV MONO THERAPY
• IV DUAL THERAPY
• COMBINATION THERAPY
• Mono or dual therapy VANCOMYCIN

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• Monotherapy IV
• Extended spectrum Antipseudomonal Cephalosporins
• Cefepime
• Ceftazidime
• Carbapenem
• Imipenem Cilastatin
• Meropenem
• Anti Pseudomonal PCN
• Piperacillin- Tazobactam
• Ticarcillin- Clavulanic acid

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DUAL therapy

• 1. an aminoglycoside
• plus
• an antipseudomonal penicillin
• (with or without a beta-lactamase
  inhibitor)
• or
• an extended-spectrum
• antipseudomonal cephalosporin,

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Dual therapy

• (2) ciprofloxacin plus an
• antipseudomonal penicillin.
• Indications
• Unstable patient
• H/O P. aeruginosa colonization or Invasive
  disease

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5 Indications for Vancomycin

• 1. clinically suspected serious catheter-related
  infections
• 2. known colonization with penicillin- and
• cephalosporin-resistant pneumococci or MRSA,
• 3. positive results of blood culture for
  gram-positive
• hypotension or other evidence of cardiovascular
  impairment
• 5. H/O ciprofloxacin or trimethoprim-sulfamethoxaz
  ole

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vancomycin resistant enterococcus

• Linezolid
• Daptomycin (avoid for pneumonia)
• Quinopristin- Dalfopristin

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PCN allergy

• NON ANAPHYLACTIC
• If not allergic to cephalosporins
• Cefepime
• ANAPHYLACTIC and allergic to cephalosporins-
• Aztreonam /- Aminoglycoside or a FQ
• /- Vancomycin if indicated

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MAINTAIN BROAD SPECTRUM ACTIVITY FOR A MINIMUM OF
7 DAYS OR UNTIL ANC gt500
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Antibiotic stopping guideIDSA, Clin Infect
Disease, 2002

• Minimum 1 week of therapy if
• Afebrile by day 3
• Neutrophils gt500/mm3 (2 consecutive days)
• Cultures negative
• Low risk patient, uncomplicated course
• gt 1 week of therapy based if
• Temps slow to settle (gt3 days)
• Continue for 4-5 days after neutrophil recovery
  (gt500/mm3 )
• Minimum 2 weeks
• Bacteraemia, deep tissue infection
• After 2 weeks if remains neutropenic (lt
  500/mm3), BUT afebrile, no disease focus, mucous
  membranes, skin intact, no catheter site
  infection, no invasive procedures or ablative
  therapy plannedcease antibiotics and observe

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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

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Antifungals

• Easy to Initiate/ Difficult to stop
• Aggressive search for Fungal Infections
• Pulmonary Aspergillosis/Sinusitis / Hepatic
  Candidiasis
• CT Chest and Abdomen
• CT Sinuses
• Cultures of suspicious skin lesions

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ANTI FUNGALS

• AMPHO B IV drug of choice for high risk patients
  
• Alternative options
• FLUCONAZOLE
• ITRACONAZOLE
• ECHINOCANDINS
• Voriconazole is NOT FDA approved for empiric
  therapy for persistent fevers in FN

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Fluconazole candida

• Fluconazole acceptable if NO
• Moulds and Resistant Candida
• ( C. Krusei and C. glabrata )
• Uncommon.
• Low risk patients

• DO NOT Use Fluconazole if
• Evidence of Sinusitis or
• Radiographic evidence of Evidence of Pulmonary
  disease
• If patient has received Fluconazole prophylaxis
  before.

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Itraconazole

• In a recent controlled study of 384 neutropenic
  patients with cancer, itraconazole and
  amphotericin B were equivalent in efficacy as
  empirical antifungal therapy.
• FOR BOARDS use AmphoB OR Itraconazole- hopefully
  should not ask you to choose between Itraconazole
  and Ampho B

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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 4010871094,2005
• 
  NEJM 353977,9881052,20
  05

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Use of Antiviral Drugs

• Antiviral drugs are not recommended for routine
  use unless clinical or laboratory evidence of
  viral infection is evident.

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• Granulocyte TransfusionsGranulocyte transfusions
  are not recommended for routine use.
• Use of Colony-Stimulating FactorsUse of
  colony-stimulating factors is not routine but
  should beconsidered in certain cases with
  predicted worsening of course.

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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

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Updates not for BOARDS but for clinical practice

• JAC 57176,2006
• A meta analysis of 33 RCTs until Feb 2005 on
  Antipseudomonal B lactams as MONOtherapies showed
  that CEFEPIME increases 30 day all cause
  mortality
• Carbapenems were associated with increased
  Pseudomembranous colitis.

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Special Situations
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Neutropenic Enterocolitis or Typhilitis

• Inflammatory process involving colon and/or small
  bowel
• ischemia, necrosis, bacteremia
• ( translocation from gut) hemorrhage, and
  perforation.
• Fever and abdominal pain ( typically RLQ).
• Bowel wall thickening on ultrasonography or CT
  imaging.

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Treatment ( 50-70 mortality)

• Initial conservative management
• bowel rest,
• intravenous fluids,
• TPN,
• broad-spectrum antibiotics
• and normalization of neutrophil counts.
• Surgical intervention
• obstruction, perforation, persistent
  gastrointestinal bleeding despite correction of
  thrombocytopenia and coagulopathy, and clinical
  deterioration.

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Consider Pseudomonal and Clostridial coverage
in Empiric therapy

• Clostridium SepticumClostridium SordelliCover
  with PEN G ,AMP, ClindamycinBroad Spectrum Abx
  ( carbapenem )include Metronidazole if unsure
  of Cdiff resistance of Clostridia to
  clindamycin reported.

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H/O leukemia and prolonged antibiotic therapy
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Angioinvasive Aspergillosis

• Confirm with Biopsy
• Aggressive Antifungal Therapy
• Voriconazole (Drug of Choice)
• Caspofungin FDA approved for Ampho and
  Voriconazole refractory Aspergillus.

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Case 1- Mr. Thomas

• June 20th 2009 diagnosed AML
• June 21st 2009 R subclavian
• Hickman placed and Chemotherapy initiated
• Remission Induction S/P 7 3 regimen Cytarabine
  (Ara C) and Daunorubicin
• June 28th 2009 - last dose of chemotherapy.
• July 10th 2009 - Febrile Neutropenia
• ANC 280 ANC lt 500 last 2 days

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• Experiences chills with CVC flushing and
  erythema and tenderness is noted over the
  hickman exit site.
• Allergies NKDA
• Labs Pancytopenic
• LFTS ok Creatinine 1.0

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What is the best next step?

• 1- Cefepime or Zosyn IV stat
• 2- Vancomycin IV stat
• 3- CXR
• 4- Blood cultures-central and peripheral
• 5- Fluconazole IV stat

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Cefepime and Vancomycin are initiated

• Blood cultures are for MRSE 2/2.
• Pt becomes afebrile day 4 of ABX.
• Surveillance Blood cultures are Negative. Patient
  is stable.
• ANC 300 by DAY 4

• What will you do next?
• A Stop Cefepime
• B Add G- CSF
• C Continue Cepepime until ANC gt 500 or a
  minimum of 7 days.
• D Continue Vancomycin for a total of 7 days.

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Remember for boards

• Do not order CT scan in a neutropenic patient
  with a normal CXR.
• In clinical practice if patient remains febrile
  for 3 to 5 days then the next step is HRCT. ( 50
  of patients with imaging have a normal CXR)

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Conclusions

• Febrile Neutropenia is a serious complication of
  chemotherapy
• Be vigilant for febrile neutropenia in
  chemotherapy patients
• Be vigilant for infection even when no fever
• Initiate EMPIRIC antibiotics immediately.
• Several treatment options depending on risk
  stratification.