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Neutropenic Fever

Aka: Neutropenic Fever, Febrile Neutropenia

I. See Also

  1. Neutropenia
  2. Neutropenia Causes
  3. Neutropenic Enterocolitis
  4. Neutropenic Fever Clinical Decision Rule (MASCC Risk Index)

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 due to risk of mucosal invasion of gut-colonizing organisms in immunocompromised host

III. Risk Factors

  1. See Neutropenia Causes

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 due to 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. Diagnosis

  1. Fever: Temperature at least 101 F (38.3 C) and
  2. Neutropenia
    1. Absolute Neutrophil Count <500/mm3
    2. Profound Neutropenia: <100 PMN/mm3

VIII. 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

IX. Labs: As Indicated

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

X. 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

XI. Evaluation

  1. See Neutropenic Fever Clinical Decision Rule (MASCC Risk Index)
    1. Use Clinical Decision Rule to define high or low risk
    2. Children under age 16 years have different rules for risk stratification
  2. High risk criteria
    1. MASCC Risk Index <21
    2. Inpatient
    3. Serum Creatinine >2 mg/dl
    4. Liver Function Tests >3 fold increased above normal
    5. Pneumonia
    6. Uncontrolled or progressive cancer
    7. Serious comorbidity
    8. Absolute Neutrophil Count <100/mm
    9. Absolute Neutrophil Count <500/mm
  3. Low risk criteria
    1. MASCC Risk Index: 21 or greater
    2. Outpatient
    3. No comorbidity
    4. Neutropenia of short duration
    5. Serum Creatinine <2 mg/dl
    6. Liver Function Tests <3 fold increased above normal
    7. Active and independent functional status
  4. References
    1. Hughes (2002) Clin Infect Dis 34:730-51 [PubMed]

XII. 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
  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

XIII. Management: Low risk (outpatient management)

  1. Precaution
    1. Only use outpatient protocol in patients risk stratified to low risk by criteria listed above
    2. Children under age 16 years have different rules for risk stratification
    3. Patients with Neutropenic Fever despite oral antibiotic prophylaxis (e.g. Levaquin) should be treated with IV antibiotic regimens below
  2. Outpatient follow-up within 3-5 days
  3. Oral antibiotics for 14 days
    1. Protocol: Single agent
      1. Levofloxacin (Levaquin) alone
    2. Protocol: Two agent (preferred)
      1. Ciprofloxacin orally and
      2. Amoxicillin-Clavulanate (Augmentin) orally

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

  1. Monotherapy (preferred)
    1. Cefepime 2 g IV every 12 hours or
    2. Ceftazidime 2 g IV every 8-12 hours or
    3. Doripenem 500 mg IV every 8 hours or
    4. Meropenem 1g IV every 8 hours or
    5. Imipenem
      1. Standard dose: 500 mg IV every 6 hours
      2. High dose (for critically ill with normal Renal Function): 500 mg IV every 4 hours or 750 mg every 6 hours
  2. Combination therapy
    1. Drug 1: Aminoglycoside
      1. Gentamicin 5.1 mg/kg IV every 24 hours or
      2. Tobramycin 5.1 mg/kg IV every 24 hours
    2. Drug 2: Piperacillin/tazobactam (Zosyn)
      1. Load: Zosyn 4.5 g IV
      2. Maintain: 3.375 g IV every 8 hours (each infused over 4 hours)
  3. Combination therapy
    1. Drug 1: Ciprofloxacin 2 g IV every 12 hours and
    2. Drug 2: Cefepime 400 mg IV every 12 hours

XV. 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 1 g IV every 12 hours

XVI. 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 3 mg mg/kg IV every 12 hours
  3. Protocol: Organism Specific
    1. Systemic Candidiasis
      1. Fluconazole or
      2. Amphoteracin B
    2. Aspergillus
      1. Voriconazole

XVII. 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

XVIII. 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) and 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)

XIX. Prognosis

  1. Mortality of untreated Febrile Neutropenia: 20-50%

XX. References

  1. (2013) Sanford Guide (electronic version 3.04b accessed 05-12-2013)
  2. Miller (2013) Crit Dec Emerg Med 27(5): 12-17
  3. Friefeld (2011) Clin Infect Dis 52(4): e56-93 [PubMed]
  4. Higdon (2006) Am Fam Physician 74:1873-80 [PubMed]
  5. Hughes (2002) Clin Infect Dis 34:730-51 [PubMed]
  6. Viscoli (1998) J Antimicrob Chemother 41:S65-80 [PubMed]

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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�減少性発熱, 発熱性好中�減少症, ｺｳ�ｭｳｷｭｳｹﾞ�ｼｮｳｾｲﾊﾂﾈﾂ, ﾊﾂﾈﾂｾｲｺｳ�ｭｳｷｭｳｹﾞ�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
Russian NEITROPENICHESKAIA LIKHORADKA, �ЕЙТРОПЕ�ИЧЕСК�Я ЛИХОР�ДК�, LIKHORADOCHNAIA NEITROPENIIA, ФЕБРИЛЬ��Я �ЕЙТРОПЕ�ИЯ, ЛИХОР�ДОЧ��Я �ЕЙТРОПЕ�ИЯ, FEBRIL'NAIA NEITROPENIIA
Derived from the NIH UMLS (Unified Medical Language System)

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