Neutropenic Fever

See Also

Precautions

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
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
Avoid Rectal Exam or Rectal Temperature
1. Risk of mucosal invasion of gut-colonizing organisms in Immunocompromised host

Pathophysiology

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

Risk Factors

See Neutropenia Causes

History
Risk Stratification

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

History
Localizing Symptoms

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

Exam

Sinusitis Findings
1. Sinus tenderness
2. Palatal or nasal invasive disease
Oral findings
1. HSV-type lesions
2. Disseminated Histoplasmosis
3. Necrotizing Gingivitis
4. Periapical Abscess
Ocular findings
1. Conjunctival Petechiae (endocarditis)
2. Roth Spots on fundus (endocarditis)
Neurologic findings
1. Altered Level of Consciousness (Meningitis)
2. Focal neurologic deficit (Brain Abscess)
Respiratory findings
1. Rhonchi or diminished breath sounds (Pneumonia)
Cardiovascular findings
1. New murmur (endocarditis)
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
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)

Causes
Common infections in Neutropenic Fever

Infection is responsible for only 20-30% of Neutropenic Fever
1. However, empiric antimicrobial management is critical until evaluation is complete
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
Fungal causes
1. Candida (more common, esp. prolonged Antibiotics, increased treatment cycles)
2. Molds (e.g. Aspergillus)
Viral causes
1. Viral Upper Respiratory Infections
2. Reactivation is most common (70% of cases)
  1. Herpes Simplex Virus
  2. Varicella Zoster Virus

Labs
Standard

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
Serum Lactic Acid
Blood Cultures (2 sets each from a different site)
1. One set should be from a central catheter site (if present)
Liver Function Tests
1. Liver transaminases
2. Serum Bilirubin
Serum Chemistry
1. Serum Electrolytes
2. Renal Function tests
  1. Blood Urea Nitrogen
  2. Serum Creatinine
Urinalysis and Urine Culture

Labs
As Indicated

Stool studies
Cerebrospinal fluid
Site-specific cultures
Respiratory viral panel

Imaging
As Indicated

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
CT Sinuses
1. Indicated for suspected Sinusitis as source of Febrile Neutropenia (especially if invasive findings)
CT Head (or MRI Brain)
1. Indicated for new neurologic changes or suspected Brain Abscess
RUQ Ultrasound
1. Indicated for suspected Ascending Cholangitis (or obstructing Cholangitis)
CT Abdomen and Pelvis
1. Indicated for suspected intraabdominal source of infection

Diagnosis

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
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

Evaluation

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
Clinical Decision Rule Scoring systems
1. See Neutropenic Fever Clinical Decision Rule (MASCC Risk Index)
2. See CISNE Score
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
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
References
1. Hughes (2002) Clin Infect Dis 34:730-51 [PubMed]

Management
General

Evaluation (see above) stratifies to high or low risk patient
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
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]
Consult patient's oncologist and consider infectious disease Consultation
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
Other medications not routinely used in Neutropenic Fever
1. Antiviral Medications (unless specifically indicated by presentation)
2. Granulocyte transfusions
3. Colony Stimulating Factors
Central venous catheter removal (suspected source) indications
1. Staphylococcus aureus
2. Pseudomonas aeruginosa
3. Candida
4. Pocket or deep infection along the Central Line

Management
Low risk (outpatient management)

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
Outpatient follow-up within 3-5 days
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)

Management
High risk - Primary protocol (inpatient)

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
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
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
Disposition: Discharge criteria
1. Afebrile for 48-72 hours AND
2. Absolute Neutrophil Count >500 cells/mm3 for 72 hours

Management
High risk - Vancomycin addition to primary protocol above

Precaution
1. Do not routinely add Vancomycin to regimen unless specifically indicated below
2. Increasing resistance (esp. Viridans Streptococcus)
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)
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

Management
High risk - Antifungal addition to primary protocol above

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)
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
Protocol: Organism Specific
1. Systemic Candidiasis
  1. Fluconazole or
  2. Amphoteracin B
2. Aspergillus
  1. Voriconazole

Management
High risk - Opportunistic organisms

See Antifungal management above
Specific gastrointestinal opportunistic infections
1. Clostridium difficile
Specific respiratory opportunistic infections
Specific neurologic opportunistic infections (present as ALOC, Seizures)
1. HSV Encephalitis
2. Toxoplasmosis

Prevention

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
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

Prognosis

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

References

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