II. Precautions

  1. Febrile Neutropenia is an Oncologic Emergency with a high mortality risk
  2. Evaluate and treat aggressively with cultures obtained and antibiotics started within 2 hours of presentation
  3. Avoid rectal exam or Rectal Temperature
    1. Risk of mucosal invasion of gut-colonizing organisms in immunocompromised host

III. Risk Factors

IV. 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

V. 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

VI. 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)

VII. Causes: Common infections in Neutropenic Fever

  1. Bacterial causes
    1. Streptococcus species (esp. S. viridans)
    2. Staphylococcus species (esp. S. epidermidis)
    3. Enterococcus
    4. Enterobacteriaceae (e.g. E. coli, Klebsiella) and other Gram Negative Rods
    5. Pseudomonas
  2. Fungal causes
    1. Candida (more common)
    2. Molds (e.g. Aspergillus)
  3. Viral causes
    1. Viral Upper Respiratory Infections (most common)
    2. Herpes Simplex Virus
    3. Varicella Zoster Virus

VIII. Diagnosis

  1. Fever
    1. Temperature 101.3 F (38.5 C) for a single axillary or oral reading OR
    2. Temperature 100.4 F (38.0 C) sustained for 1 hour
  2. Neutropenia
    1. Absolute Neutrophil Count <500/mm3 (or expected to decrease to this level within 48 hours)
    2. Profound Neutropenia: <100 PMN/mm3

IX. Labs: Standard

  1. Complete Blood Count with differential
    1. Determine Absolute Neutrophil Count (ANC)
    2. Neutropenia: <500 PMN/mm3
    3. Profound Neutropenia: <100 PMN/mm3
  2. Blood Cultures (2 sets each from a different site)
    1. One set should be from a central catheter site (if present)
  3. Liver Function Tests
    1. Liver transaminases
    2. Serum Bilirubin
  4. Serum Chemistry
    1. Serum Electrolytes
    2. Renal Function tests
      1. Blood Urea Nitrogen
      2. Serum Creatinine

X. Labs: As Indicated

  1. Urinalysis and Urine Culture
  2. Stool studies
  3. Cerebrospinal fluid
  4. Site-specific cultures

XI. Imaging: As Indicated

  1. Chest XRay
    1. Indicated for respiratory symptoms or source not readily apparent
  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. 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
    9. Clinically unstable
    10. Absolute Neutrophil Count <100/mm3 for >7 days (profound Neutropenia)
  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 comorbidity
    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
  5. References
    1. Hughes (2002) Clin Infect Dis 34:730-51 [PubMed]

XIII. 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. Early antibiotics (preferably within 30 minutes of presentation) have highest survival
    2. 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

XIV. 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
  2. Outpatient follow-up within 3-5 days
  3. Oral antibiotics for 14 days
    1. 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)
    2. Protocol: Single agent
      1. Moxifloxacin (preferred) 400 mg orally daily OR
      2. Levofloxacin (Levaquin)

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

  1. Monotherapy (preferred)
    1. Cefepime 2 g IV every 8 hours or
    2. Ceftazidime 2 g IV every 8-12 hours or
    3. Doripenem 500 mg IV every 8 hours or
    4. Meropenem 1-2g IV every 8 hours or
    5. Imipenem 500 mg IV every 6 hours (every 4 hours if critically ill with normal Renal Function)
  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)
  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

XVI. 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 catheter related infection
    3. Patient known to be colonized
      1. Methicillin Resistant Staphlyococcus aureus (MRSA)
      2. Penicillin Resistant Pneumococcus (PRP)
      3. Cephalosporin-resistant pneumococci
    4. Initial Blood Cultures positive for Gram Positives
    5. Cardiovascular compromise
  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

XVII. 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

XVIII. 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

XIX. 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

XX. Prognosis

  1. Mortality of untreated Febrile Neutropenia in high risk patients: 20-50%

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Ontology: Febrile Neutropenia (C0746883)

Definition (MSH) Fever accompanied by a significant reduction in the number of NEUTROPHILS.
Definition (NCI) Neutropenia associated with fever, the latter indicating the presence of an infection.
Definition (NCI_CTCAE) A disorder characterized by a decrease in neutrophils associated with fever.
Definition (NCI_NCI-GLOSS) A condition marked by fever and a lower-than-normal number of neutrophils in the blood. A neutrophil is a type of white blood cell that helps fight infection. Having too few neutrophils increases the risk of infection.
Concepts Disease or Syndrome (T047)
MSH D064147
SnomedCT 409089005
Dutch neutropene koorts, febriele neutropenie
French Fièvre neutropénique, Neutropénie fébrile
German neutropenisches Fieber, Febrile Neutropenie, febrile Neutropenie
Italian Febbre neutropenica, Neutropenia febbrile
Portuguese Febre neutropénica, Neutropenia febril
Spanish Fiebre por neutropenia, Neutropenia febril, neutropenia febril (trastorno), neutropenia febril
Japanese 好中球減少性発熱, 発熱性好中球減少症, コウチュウキュウゲンショウセイハツネツ, ハツネツセイコウチュウキュウゲンショウショウ
English neutropenic fever (diagnosis), neutropenic fever, fever neutropenic, febrile neutropenia, neutropenia febrile, neutropenia fever, fever neutropenia, Neutropenic fever, Febrile Neutropenia, Neutropenias, Febrile, Neutropenia, Febrile, Febrile Neutropenias, Febrile Neutropenia [Disease/Finding], Febrile neutropenia, Febrile neutropenia (disorder)
Czech Febrilní neutropenie, febrilní neutropenie
Hungarian Neutropeniás láz, lázas neutropenia