Neutropenic Fever

Aka: Neutropenic Fever, Febrile Neutropenia

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II. Precautions

  1. Febrile Neutropenia is an Oncologic Emergency with a high mortality risk
    1. Fever is the earliest and possibly the only symptom on presentation of serious infection in Neutropenia
  2. Evaluate and treat aggressively with cultures obtained and Antibiotics started within 2 hours of presentation
    1. Gram Negative are the most common and most deadly causes of Neutropenic Fever
    2. Neutropenic patients are also higher risk for resistant and opportunistic infections
  3. Avoid Rectal Exam or Rectal Temperature
    1. Risk of mucosal invasion of gut-colonizing organisms in Immunocompromised host

III. Pathophysiology

  1. Chemotherapy suppresses myelopoiesis or granulopoiesis (Granulocyte maturation), most notably Neutrophils
  2. Chemotherapy disrupts gastrointestinal mucosa and allows for microbial translocation
  3. Chemotherapy blunts the inflammatory response resulting in few symptoms of serious infection beyond fever

IV. Risk Factors

  1. See Neutropenia Causes

V. History: Risk Stratification

  1. Malignancy Type
  2. Current radiation (and last dose)
  3. Current Chemotherapy (and last dose)
  4. Prior Neutropenia
  5. Current Antibiotics
  6. Comorbid illness (e.g. Diabetes Mellitus)
  7. New onset red flag symptoms and signs
    1. Hypotension
    2. Abdominal Pain
    3. Neurologic changes

VI. History: Localizing Symptoms

  1. CNS symptoms
    1. Headache
    2. Neck stiffness
    3. Altered Level of Consciousness
  2. HEENT symptoms
    1. Sinus pressure
    2. Post-nasal drainage
    3. Oral Lesions (HSV, Candidiasis)
    4. Dysphagia or odynophagia (Esophageal Candidiasis, HSV)
  3. Respiratory symptoms
    1. Cough
    2. Shortness of Breath
    3. Pleuritic Chest Pain
  4. Cardiovascular
    1. Hypotension or Light Headedness on standing
  5. Gastrointestinal symptoms
    1. Abdominal Pain
    2. Diarrhea
  6. Genitourinary symptoms
    1. Dysuria
    2. Urinary urgency or frequency
    3. Hematuria
  7. Skin
    1. Skin Lesions
    2. Skin or mucosal tears or Lacerations
    3. Indwelling ports or catheters

VII. Exam

  1. Sinusitis Findings
    1. Sinus tenderness
    2. Palatal or nasal invasive disease
  2. Oral findings
    1. HSV-type lesions
    2. Disseminated Histoplasmosis
    3. Necrotizing Gingivitis
    4. Periapical Abscess
  3. Ocular findings
    1. Conjunctival Petechiae (endocarditis)
    2. Roth Spots on fundus (endocarditis)
  4. Neurologic findings
    1. Altered Level of Consciousness (Meningitis)
    2. Focal neurologic deficit (Brain Abscess)
  5. Respiratory findings
    1. Rhonchi or diminished breath sounds (Pneumonia)
  6. Cardiovascular findings
    1. New murmur (endocarditis)
  7. Gastrointestinal findings
    1. Precautions
      1. Avoid Rectal Exam or Rectal Temperature
        1. Risk of mucosal invasion of gut-colonizing organisms in Immunocompromised host
    2. Obstructing Cholangitis
      1. Patients with intraabdominal solid tumors
    3. Neutropenic Enterocolitis
      1. Diarrhea, Abdominal Pain and fever in patients with Leukemia
    4. Perirectal Abscess
  8. Skin findings
    1. Skin Tears or Lacerations
    2. Decubitus Ulcers
    3. Cellulitis
    4. Indwelling ports and catheter site inflammation
    5. Hemorrhagic Nodules on palms and soles (Janeway Lesions in endocarditis)
    6. Nail Splinter Hemorrhages (endocarditis)

VIII. Causes: Common infections in Neutropenic Fever

  1. Infection is responsible for only 20-30% of Neutropenic Fever
    1. However, empiric antimicrobial management is critical until evaluation is complete
  2. Bacterial causes
    1. Gram Positive Bacteria (60% of causes in U.S., increased with longterm venous catheters, new Chemotherapy)
      1. Streptococcus species (esp. S. viridans)
      2. Staphylococcus species (esp. S. epidermidis)
      3. Enterococcus
    2. Gram Negative Bacteria (more common prior to 2000)
      1. Enterobacteriaceae (e.g. E. coli, Klebsiella) and other Gram Negative Rods
      2. Pseudomonas
  3. Fungal causes
    1. Candida (more common, esp. prolonged Antibiotics, increased treatment cycles)
    2. Molds (e.g. Aspergillus)
  4. Viral causes
    1. Viral Upper Respiratory Infections
    2. Reactivation is most common (70% of cases)
      1. Herpes Simplex Virus
      2. Varicella Zoster Virus

IX. Labs: Standard

  1. Complete Blood Count with differential
    1. Determine Absolute Neutrophil Count (ANC) which includes both PMNs as well as Band Neutrophils
    2. Absolute Neutrophil Count reaches nadir at 12-14 days after Chemotherapy
    3. Absolute Neutrophil Count <1500 PMN/mm3 is consistent with Neutropenia
    4. Severe Neutropenia: <500 PMN/mm3
    5. Profound Neutropenia: <100 PMN/mm3
  2. Serum Lactic Acid
  3. Blood Cultures (2 sets each from a different site)
    1. One set should be from a central catheter site (if present)
  4. Liver Function Tests
    1. Liver transaminases
    2. Serum Bilirubin
  5. Serum Chemistry
    1. Serum Electrolytes
    2. Renal Function tests
      1. Blood Urea Nitrogen
      2. Serum Creatinine
  6. Urinalysis and Urine Culture

X. Labs: As Indicated

  1. Stool studies
  2. Cerebrospinal fluid
  3. Site-specific cultures
  4. Respiratory viral panel

XI. Imaging: As Indicated

  1. Chest XRay
    1. Indicated for respiratory symptoms or source not readily apparent
    2. Chest XRay may be unreliable with lack of infiltrates due to poor inflammatory cell response
      1. Have a high index of suspicion for Pneumonia when clinical diagnosis is suspected
  2. CT Sinuses
    1. Indicated for suspected Sinusitis as source of Febrile Neutropenia (especially if invasive findings)
  3. CT Head (or MRI Brain)
    1. Indicated for new neurologic changes or suspected Brain Abscess
  4. RUQ Ultrasound
    1. Indicated for suspected Ascending Cholangitis (or obstructing Cholangitis)
  5. CT Abdomen and Pelvis
    1. Indicated for suspected intraabdominal source of infection

XII. Diagnosis

  1. Fever
    1. Temperature obtained via tympanic, oral or Axillary Temperature
      1. Avoid Oral Temperature when mucositis is present
      2. Avoid Rectal Temperature in Neutropenia
    2. Temperature >100.9 F (38.3 C) for a single reading OR
    3. Temperature >100.4 F (38.0 C) sustained for 1 hour
  2. Neutropenia
    1. Absolute Neutrophil Count (ANC) <1000/mm3 with expected decrease to <500/mm3 within 48 hours OR
    2. Absolute Neutrophil Count (ANC) <500/mm3
      1. Profound Neutropenia: ANC <100 PMN/mm3

XIII. Evaluation

  1. Precautions
    1. Use Clinical Decision Rule to define high or low risk
    2. Children under age 16 years have different rules for risk stratification
    3. Liquid Tumors (blood or Bone Marrow cancers)
      1. Higher risk of Neutropenic Fever complications than solid tumors
  2. Clinical Decision Rule Scoring systems
    1. See Neutropenic Fever Clinical Decision Rule (MASCC Risk Index)
    2. See CISNE Score
  3. High risk criteria
    1. MASCC Risk Index <21
    2. CISNE Score >3 (moderate risk if score 1-2)
    3. Inpatient
    4. Serum Creatinine >2 mg/dl
    5. Liver Function Tests >3 fold increased above normal
    6. Pneumonia
    7. Uncontrolled or progressive cancer
    8. Serious comorbidity (e.g. COPD)
    9. Organ dysfunction
    10. Hemodynamic instability (e.g. Hypotension, Dehydration) or otherwise clinically unstable
    11. Severe Neutropenia <500/mm3, esp. profound Neutropenia <100/mm3, and esp. >7 days
  4. Low risk criteria
    1. MASCC Risk Index: 21 or greater
    2. CISNE Score 0
      1. More accurate than MASCC Risk Index in identifying low risk patients
      2. Coyne (2016) Ann Emerg Med 69(6): 755-64 +PMID: 28041827 [PubMed]
    3. Outpatient
    4. No serious comorbidity (e.g. COPD)
    5. Neutropenia of short duration
    6. Serum Creatinine <2 mg/dl
    7. Liver Function Tests <3 fold increased above normal
    8. Active and independent functional status
    9. Age <60 years old
  5. References
    1. Hughes (2002) Clin Infect Dis 34:730-51 [PubMed]

XIV. Management: General

  1. Evaluation (see above) stratifies to high or low risk patient
  2. Approach if Fever at home but not at medical encounter
    1. Pediatrics: Manage based on fever at home
    2. Adults: Consider managing based on the low risk protocol
  3. Evaluate and treat aggressively with cultures obtained and Antibiotics started within 2 hours of presentation
    1. HIgh risk patients should receive Antibiotics within first hour of presentation
    2. Early Antibiotics (preferably within 30 minutes of presentation) have highest survival
    3. Rosa (2014) Antimicrob Agents Chemother 58(7): 3799-803 [PubMed]
  4. Consult patient's oncologist and consider infectious disease Consultation
  5. Antimicrobial selection
    1. Based on evaluation and risk-stratified approaches below
    2. Indication for Vancomycin protocol as listed below
    3. Consider Antifungals if no improvement in 3 days
  6. Other medications not routinely used in Neutropenic Fever
    1. Antiviral Medications (unless specifically indicated by presentation)
    2. Granulocyte transfusions
    3. Colony Stimulating Factors
  7. Central venous catheter removal (suspected source) indications
    1. Staphylococcus aureus
    2. Pseudomonas aeruginosa
    3. Candida
    4. Pocket or deep infection along the Central Line

XV. Management: Low risk (outpatient management)

  1. Precaution
    1. Only use outpatient protocol in patients risk stratified to low risk by criteria listed above
    2. Patient should be compliant with easy access to follow-up and emergency care
    3. Children under age 16 years have different rules for risk stratification
    4. Patients with Neutropenic Fever despite oral Antibiotic prophylaxis (e.g. Levaquin)
      1. Treat with IV Antibiotic regimens below
    5. Outpatient management in low risk patients is successful in 80% of cases
      1. Readmission will be required in 20% of cases
      2. Failed outpatient management predictors
        1. Age >70 years old
        2. Poor home functional status
        3. Severe mucositis
        4. Absolute Neutrophil Count <100/mm3
  2. Outpatient follow-up within 3-5 days
  3. Oral Antibiotics for 14 days
    1. All outpatient protocols use Fluoroquinolones
      1. Advise patients regarding potential Fluoroquinolone adverse effects
    2. Protocol: Two agent (preferred)
      1. Ciprofloxacin 750 mg orally twice daily AND
      2. Amoxicillin-Clavulanate (Augmentin) 875 mg bid (or Clindamycin 300 mg PO q6-8h)
    3. Protocol: Single agent
      1. Moxifloxacin (preferred) 400 mg orally daily OR
      2. Levofloxacin (Levaquin)

XVI. Management: High risk - Primary protocol (inpatient)

  1. Monotherapy (preferred)
    1. Cefepime 2 g IV every 8 hours or
    2. Doripenem 500 mg IV every 8 hours or
    3. Meropenem 1-2g IV every 8 hours or
    4. Imipenem 500 mg IV every 6 hours (every 4 hours if critically ill with normal Renal Function) or
    5. Ceftazidime 2 g IV every 8-12 hours
      1. Gram Negative Bacteria resistance
      2. Incomplete Gram Positive Bacteria coverage
  2. Additional agent indications (to be used in combination with monotherapy agents above)
    1. See Vancomycin indications below
    2. See Antifungal indications below
    3. Consider combination protocol in hemodynamically Unstable Patients
      1. Cefepime (or other agent from monotherapy list) AND
      2. Tobramycin 5.1 mg/kg IV every 24 hours AND
      3. Vancomycin (see below for dosing) AND
      4. Antifungal (see below for agents)
    4. Anaerobic coverage indications
      1. Intraabdominal or pelvic infections
      2. Sinusitis
      3. Perirectal Cellulitis
  3. Other combination regimens that have been used historically
    1. Tobramycin 5.1 mg/kg IV q24h AND Piperacillin/tazobactam (Zosyn) 4.5 g IV, then 3.375 g IV q8h OR
    2. Cefepime 2 g IV q8h AND Ciprofloxacin 400 mg IV q12h
  4. Disposition: Discharge criteria
    1. Afebrile for 48-72 hours AND
    2. Absolute Neutrophil Count >500 cells/mm3 for 72 hours

XVII. Management: High risk - Vancomycin addition to primary protocol above

  1. Precaution
    1. Do not routinely add Vancomycin to regimen unless specifically indicated below
    2. Increasing resistance (esp. Viridans Streptococcus)
  2. Indications for Vancomycin
    1. Inpatient setting where MRSA is common
    2. Serious central venous catheter related infection
    3. Skin or soft tissue infections
    4. Pneumonia or muscositis
    5. Patient known to be colonized
      1. Methicillin Resistant Staphlyococcus aureus (MRSA)
      2. Penicillin Resistant Pneumococcus (PRP)
      3. Cephalosporin-resistant pneumococci
    6. Initial Blood Cultures positive for Gram Positives
    7. Cardiovascular compromise (Septic Shock)
  3. Protocol
    1. Primary Monotherapy or Combination therapy regimen as above AND
    2. Vancomycin 15-20 mg/kg IV every 8-12 hours
      1. Linezolid 600 mg IV or oral every 12 hours may be used in place of Vancomycin

XVIII. Management: High risk - Antifungal addition to primary protocol above

  1. Indications
    1. Profound Neutropenia (<100 pmn/mm3) for longer than 10 days
    2. Acute myeloginous Leukemia
    3. Myelodysplastic Syndrome
    4. Graft-versus-host disease
    5. Hematopoietic Stem Cell Transplant
    6. Fever >4 days despite Antibiotics
    7. 'Halo Sign' (Nodule surrounded by edema or blood) on maxillofacial CT or Chest CT (Aspergillosis)
    8. Bony erosions on maxillofacial CT (Aspergillus or Zygomycota)
    9. Candidiasis (skin or systemic Candidiasis)
  2. Protocol: Empiric Antifungals
    1. Precaution: Risk of Drug Interactions (consult with pharmacy)
    2. Caspofungin 70 mg IV on day 1, then 50 mg IV every 24 hours or
    3. Micafungin 100 mg IV every 24 hours or
    4. Anidulafungin 200 mg IV for 1 dose, then 100 mg IV every 24 hours or
    5. Voriconazole 6 mg/kg IV every 12 hours for 2 doses, then 4 mg mg/kg IV every 12 hours
      1. Consider Voriconazole if fever occurred while on anti-candida prophylaxis
  3. Protocol: Organism Specific
    1. Systemic Candidiasis
      1. Fluconazole or
      2. Amphoteracin B
    2. Aspergillus
      1. Voriconazole

XIX. Management: High risk - Opportunistic organisms

  1. See Antifungal management above
  2. Specific gastrointestinal opportunistic infections
    1. Clostridium difficile
  3. Specific respiratory opportunistic infections
    1. Aspergillus
    2. Cryptococcus
    3. Histoplasmosis
    4. Coccidiomycosis
    5. Pneumocystis jiroveci Pneumonia
    6. Tuberculosis
  4. Specific neurologic opportunistic infections (present as ALOC, Seizures)
    1. HSV Encephalitis
    2. Toxoplasmosis

XX. Prevention

  1. Medical Providers
    1. Prevent in-hospital transmission by Hand Washing before and after patient care
    2. Barrier precautions are specific to the presenting cause (e.g. Pneumonia)
      1. Not otherwise specifically indicated for Neutropenia
  2. Neutropenic Patients
    1. Avoid eating raw foods, yogurt, and exposure to fresh flowers (little to no evidence of benefit)
    2. Granulocyte Colony Stimulating Factors
      1. Indicated if Neutropenic Fever risk >20% (or >10% if age >65 or serious comorbidity)
      2. Agents: Filgrastim or Pegfilgrastim
    3. Antimicrobials
      1. See other references for prophylaxis indications and the specific agents used
      2. Antibacterial prophylaxis (e.g. Levaquin, cipro) if expected ANC <100 mm3 for >7 days
      3. Anti-candidal, anti-Aspergillus and Antiviral prophylaxis also have specific indications

XXI. Prognosis

  1. Mortality of untreated Febrile Neutropenia in high risk patients: 20-70%

XXII. References

  1. (2016) Sanford Guide to Antibiotics, IOS app accessed 4/14/2016
  2. Long, Long and Koyfman (2020) Crit Dec Emerg Med 34(11): 17-24
  3. Miller (2013) Crit Dec Emerg Med 27(5): 12-17
  4. Friefeld (2011) Clin Infect Dis 52(4): e56-93 [PubMed]
  5. Higdon (2018) Am Fam Physician 97(11):741-8 [PubMed]
  6. Higdon (2006) Am Fam Physician 74:1873-80 [PubMed]
  7. Hughes (2002) Clin Infect Dis 34:730-51 [PubMed]
  8. Viscoli (1998) J Antimicrob Chemother 41:S65-80 [PubMed]

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