Neutropenic Fever

Neutropenic fever is a medical emergency defined as a fever > 38.3℃ (100.9℉) or higher than 38.0℃ (100.4℉) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Patients are often asymptomatic, and the only sign is the presence of fever. Diagnosis should include a detailed history, physical examination, and routine laboratory tests, in addition to symptom-directed workup with cultures. Initial management includes the administration of empiric antibiotics adjusted according to clinical response and culture results.

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Overview

Definition

Neutropenic fever is defined as a single oral temperature > 38.3℃ (100.9℉) or a temperature > 38.0℃ (100.9℉) for at least 1 hour with an absolute neutrophil count (ANC) of < 1500 cells/µL or an ANC that is expected to decrease to < 500 cells/µL during the next 48 hours.

Epidemiology

  • Febrile neutropenia develops in:
    • 10%–50% of patients with solid tumors
    • 80% of patients with hematologic tumors
  • 50% of patients will develop an infection.
  • Source of infection evident in 20%–30% of cases
  • Examination/culture fail to detect infectious focus/pathogen in 30%–60% of cases.
  • Common sites of infection include: 
    • Lung
    • Skin
    • Blood
    • GI tract

Etiology

In most cases, the source of infection is unknown (referred to as fever of unknown origin (FUO)). The majority of documented infections are bacterial.

The common sources of bacteremia are:

  • Translocation of enteric bacteria into the bloodstream
  • Catheter-related bloodstream infections

Common bacterial pathogens:

  • Gram-positive:
    • Coagulase-negative staphylococci (most common)
      • Staphylococcus epidermidis 
      • Staphylococcus haemolyticus
    • Staphylococcus aureus (including MRSA)
    • Enterococci (including vancomycin-resistant)
    • Viridans group streptococci
    • Streptococcus pyogenes
    • Streptococcus pneumoniae
    • Bacillus species
  • Gram-negative:
    • Escherichia coli
    • Pseudomonas aeruginosa
    • Klebsiella species
    • Enterobacter
    • Fusobacterium
    • Acinetobacter species
    • Stenotrophomonas maltophilia

Common fungal pathogens:

  • Aspergillus species
  • Candida species
  • Fusarium species
  • Endemic fungi

Common viral pathogens:

  • Herpes simplex virus
  • CMV
  • Influenza virus
  • Parainfluenza virus
  • Adenovirus
  • Respiratory syncytial virus

Common parasitic pathogens:

  • Strongyloidiasis
  • Leishmaniasis
  • Trypanosomiasis

Pathophysiology

The combination of the following factors contribute to the development of neutropenic fever:

  • Chemotherapy-induced bone marrow suppression 
  • Metastatic replacement of bone marrow
  • Chemotherapy-induced mucosal injury
  • Presence of infection sources (indwelling catheters)
Peripheral blood smear showing normochromic RBCs with anisocytosis:poikilocytosis - neutropenia

Peripheral blood smear showing a paucity of neutrophils

Image: “Peripheral blood smear” by Melissa Zhao. License: CC BY 4.0

Clinical Presentation

Neutropenia may minimize symptoms and signs of infection:

  • Neutrophil activation responsible for many inflammatory symptoms of infection
  • Neutropenia → ↓ neutrophil activation → ↓ cytokine release → ↓ inflammatory symptoms

The presence of fever may be the only sign of an infection.

Common symptoms of febrile neutropenia are:

  • Odynophagia
  • Sore mouth
  • Skin ulcers
  • Cough
  • Dyspnea
  • Dysuria
  • Urinary frequency and urgency
  • Redness and tenderness at the catheter site

Diagnosis

All patients with febrile neutropenia should undergo a detailed history and physical examination, and diagnostic studies should be performed.

History

A detailed history should include:

  • Review of systems to locate an infection focus
  • Current medications
  • Type of cancer
  • Current chemotherapy regimen
  • Presence of allergies
  • Steroid use
  • Comorbidities
  • Prior history of infections
  • Recent prophylaxis with antibiotics 
  • Recent administration of hematopoietic growth factors
  • History of transplantation

Physical exam

A thorough physical examination should include an evaluation of:

  • Skin:
    • Erythema 
    • Tenderness
    • Ulcers
    • Abscesses
    • Central catheter insertion sites
    • Ecthyma gangrenosum (seen in P. aeruginosa infection)
  • Optic fundi: signs of septic emboli
  • Sinuses
  • Mouth:
    • Ulcers
    • Periodontal disease
    • Leukoplakia
  • Lungs
  • Abdomen:
    • Visceral mucosal examination
    • Do not perform rectal exam in neutropenic patients.
  • Perineal area:
    • Pilonidal cyst
    • Perirectal abscess
    • Vaginal/vulvar infection
  • Neurologic system:
    • Meningismus
    • Focal neurologic deficit
    • Altered mental status
  • Catheter sites:
    • Erythema
    • Fluctuance
    • Tenderness
    • Palpable cord along the vein

Diagnostic testing

Laboratory studies:

  • CBC/DIFF:
    • Severe neutropenia: ANC < 500 cells/µL
    • Profound neutropenia: ANC < 100 cells/µL
  • Blood type
  • Coagulation studies
  • Chemistry panel:
    • Renal function
    • Hepatic function
    • Electrolytes
  • Lactate: Increased levels suggest sepsis.
  • Urinalysis 
  • CRP
  • ESR
  • Procalcitonin (PCT):
    • Prohormone of calcitonin, produced during systemic infection in response to microbial toxins and host inflammatory mediators
    • May help differentiate infectious from noninfectious etiology of fever:
      • Elevated in bacterial infection
      • Elevated in fungal infection
    •  May help guide selection and duration of antibiotic therapy:
      • Strengthens decision for antibiotic initiation if elevated
      • Strengthens decision to withhold/withdraw antibiotics if not elevated
    • May help prevent unnecessary/prolonged antibiotic therapy

Culture:

  • Blood culture:
    • 2 sets of blood cultures should be obtained from 2 separate peripheral venipuncture sites and from any indwelling venous catheter.
    • 1 set consists of 2 bottles (aerobic and anaerobic).
  • Urine culture should be obtained if:
    • Patient is symptomatic
    • Patient has a history of urinary tract infection
    • Catheter is present
  • Site-specific culture
    • Stool microscopy and culture if diarrhea is present (Clostridium difficile)
    • Sputum microscopy and culture if signs of respiratory infection are present
    • Skin/wound swab

Imaging:

  • A chest X-ray or CT scan should be obtained. 
  • Further imaging should be performed when clinically indicated.

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Management

General approach

  • Risk assessment considerations:
    • Multinational Association for Supportive Care in Cancer (MASCC) score
    • Appropriate for outpatient versus inpatient management
    • Appropriate for oral versus IV antibiotics
    • Anticipated duration of therapy
    • Caregiver availability
  • Low-risk patients:
    • Neutropenia duration ≤ 7 days
    • No comorbidities
    • Normal hepatic and renal functions
    • MASCC score ≥ 21 
  • High-risk patients:
    • Profound neutropenia (ANC ≤ 100 cells/µL)
    • Prolonged neutropenia (≥ 7 days)
    • Current fluoroquinolone prophylaxis
    • MASCC score ≤ 21
    • Comorbid conditions:
      • New-onset abdominal pain
      • Hypotension 
      • Pneumonia
      • Neurologic changes
      • Laboratory evidence of organ dysfunction
      • Hemodynamic instability
  • Empiric therapy should be administered within 1 hour after admission.
  • Empiric antibiotics selection:
    • Tailored to known/suspected source of infection
    • Antipseudomonal beta-lactam antibiotic for patients already on fluoroquinolone prophylaxis
    • If source unknown:
      • Broad-spectrum coverage
      • Consider infectious disease consultation.
Table: Multinational Association for Supportive Care in Cancer (MASCC) risk index score
CharacteristicScore
Burden of illness: no or mild symptoms5
Burden of illness: moderate symptoms3
Burden of illness: severe symptoms0
No hypotension5
No chronic obstructive pulmonary disease4
Solid tumor or hematologic malignancy with no previous fungal infection4
No dehydration requiring parenteral fluids3
Outpatient status2
Age < 60 years2

Low-risk patients

Low-risk patients are treated as outpatients or initially as inpatients and then transferred to outpatient with close follow-up (oral antibiotic therapy).

  • No penicillin allergy: levofloxacin/ciprofloxacin plus amoxicillin–clavulanate
  • Penicillin allergy: clindamycin plus levofloxacin/ciprofloxacin
  • Other: moxifloxacin monotherapy
  • No antifungal treatment is recommended initially.
  • Broad-spectrum antifungals should be administered if fever persists ≥ 4–7 days.

High-risk patients

High-risk patients must be treated as inpatients (IV antibiotic therapy).

  • No penicillin allergy:
    • Piperacillin–tazobactam
    • Meropenem
    • Imipenem–cilastatin
    • Cefepime
  • Complicated case or antibiotic resistance: Aminoglycosides should be added to the above regimens.
    • Gentamicin
    • Amikacin
    • Tobramycin
  • Penicillin allergy:
    • Not on fluoroquinolone prophylaxis: ciprofloxacin plus clindamycin
    • On fluoroquinolone prophylaxis: aztreonam plus vancomycin
  • Patients with neutropenic enterocolitis:
    • Piperacillin–tazobactam
    • Carbapenem
    • Antipseudomonal cephalosporin plus metronidazole
  • Drug-resistant organisms:
    • Methicillin-resistant S. aureus:
      • Daptomycin
      • Linezolid
      • Vancomycin
    • Vancomycin-resistant enterococcus (VRE):
      • Daptomycin
      • Linezolid
    • ESBL:
      • A carbapenem
    • Klebsiella pneumoniae carbapenemase (KPS):
      • Polymyxin B
      • Colistin
      • Tigecycline
  • Indications of vancomycin addition:
    • Hemodynamic instability
    • Pneumonia
    • Blood cultures positive for gram-positive bacteria
    • Skin or soft tissue infection
    • Catheter-related infection
    • Colonization with MRSA, penicillin-resistant Streptococcus
  • Antifungal therapy:
    • Indications:
      • The patient is unstable and 
      • Fever persists > 4–7 days
    • Medications:
      • Amphotericin B (invasive aspergillosis)
      • Voriconazole (invasive aspergillosis)
      • Itraconazole
      • Posaconazole
      • Caspofungin (candidiasis)
      • Micafungin
  • Antiviral therapy:
    • Indications:
      • Active viral disease with herpes simplex/varicella zoster
      • Recent/current bone marrow transplantation
    • Medications
      • Acyclovir herpes simplex
      • Acyclovir for varicella zoster 
      • Neuraminidase inhibitors for suspected/confirmed influenza

Duration of therapy

  • Source of infection is identified:
    • Appropriate treatment duration for that particular infection and
    • ANC ≥ 500 cells/µL
  • Source of infection unknown:
    • Resolved fever ≥ 48 hours and
    • ANC ≥ 500 cells/µL

Supportive care

  • IV fluids
  • CSF administration not recommended
  • Indications for indwelling catheter removal:
    • Catheter tunnel or port pocket infection
    • Sepsis (if infectious source unknown)
    • Endocarditis
    • Septic emboli
    • Infection that persists > 72 hours despite antibiotic therapy
    • Infection caused by:
      • S. aureus
      • Streptococcus
      • Fungi
      • Nontuberculous mycobacteria

Prophylaxis

  • Indications:
    • High-risk patients
    • Profound neutropenia
    • Prolonged neutropenia
  • Medications:
    • Levofloxacin
    • Ciprofloxacin
    • Cefdinir
    • Cefpodoxime
    • Azoles
    • Trimethoprim–sulfamethoxazole (Pneumocystis jirovecii pneumonia)

Differential Diagnosis

  • Transfusion reaction: complication of transfusion therapies (blood products/whole blood). Transfusion reaction presents with fever, chills, urticaria, itching, dyspnea, hypotension, and respiratory distress. Diagnosis is based on emergence of symptoms during or after the transfusion. Management includes stopping the transfusion, administration of IV fluids, antihistamines, and antipyretics.
  • Neoplastic fever: paraneoplastic syndrome caused by certain malignancies (mostly hematologic). The only presenting symptom is fever, without signs of an infection or drug reaction. Neoplastic fever is a diagnosis of exclusion. Naproxen administration may suppress the temperature. Management includes treatment of the underlying malignancy and symptom control with NSAIDs, acetaminophen, and corticosteroids.

References

  1. Baluch, A., Shewayish, S. (2019). Neutropenic Fever. In: Infections in Neutropenic Cancer Patients. Pages 105–117. https://doi.org/10.1007/978-3-030-21859-1_8
  2. Freifeld, A. G. et al. (2011). Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases society of America. Clinical Infectious Diseases 52(4):e56–e93. https://doi.org/10.1093/cid/cir073
  3. Denshaw-Burke, M. (2019). Neutropenic fever empiric therapy. Medscape. Retrieved June 3, 2021, from https://emedicine.medscape.com/article/2012185-overview
  4. Foggo, V., Cavenagh, J. (2015). Malignant causes of fever of unknown origin. Clinical Medicine 15(3):292–294. https://doi.org/10.7861/clinmedicine.15-3-292
  5. Robinson, J. O., Lamoth, F., Bally, F., Knaup, M., Calandra, T., Marchetti, O. (2011). Monitoring procalcitonin in febrile neutropenia: what is its utility for initial diagnosis of infection and reassessment in persistent fever?. PloS One 6(4):e18886. https://doi.org/10.1371/journal.pone.0018886

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