Neutropenic fever

Chemotherapy

Radiation therapy to the bone marrow

Genetic mutations

Transient infections

Autoimmune

Drug induced

Nutritional deficiency

Marrow infiltration and destruction

Reticuloendothelial sequestration

Presentation

Classic presentation

Without adequate neutrophils, patients can have a blunted inflammatory response to infections. Examples of this are:
- Urinary tract infection without pyuria
- CNS infection without nuchal rigidity or focal neurological signs
- Pneumonia without chest radiograph abnormalities
- Skin and soft tissue infections without erythema.
Patients can present with relatively mild symptoms, sometimes with little more than a fever.
The majority do not present with a clear etiology on history or physical examination.
The most common sources of infection are
- The urinary tract
- The gastrointestinal tract
- The lungs
- Indwelling vascular access sites.
Febrile neutropenia is most common 7–14 days after chemotherapy, as this is typically the nadir of a patient’s white cell count in response to the chemotherapy.
The most commonly cultured bacteria in febrile neutropenia are Gram-negative aerobes (e.g., Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa), frequently from GI translocation. Antibiotic coverage appropriate for Pseudomonas is always necessary.

Critical presentation

The initial presentation of the critically ill with neutropenic fever may be overt with a clinical presentation similar to that of septic shock and including hypotension, respiratory failure, or any other major organ dysfunction.
It may also be cryptogenic with isolated confusion, coagulopathy, or cardiac arrhythmias.
Elderly patients and those taking steroids may present as hypothermic or euthermic. Any unexplained acute clinical deterioration should be considered a fever equivalent.
Critically ill patients with neutropenic fever will most frequently present with common infections. However, their immunocompromised state places them at risk for more complex disease processes of almost any organ system.
Although less commonly, these patients are at increased risk of infection from disseminated tuberculosis, candidiasis, Nocardia, Aspergillosis, Fusarium species, and Pneumocystis jiroveci.

Diagnosis and evaluation

Fever is defined by one temperature reading higher than 38.5°C (101.3°F) or two temperatures >38°C (100.4°F) 1 hour apart. Fevers documented at home by a patient should be accepted as true temperatures.
Neutropenia is stratified by varying degrees of absolute neutrophil count (ANC):
- ANC = WBC count × percentage of neutrophils and bands
- Mild neutropenia: ANC = 1000−1500
- Moderate neutropenia: ANC = 500−1000
- Severe neutropenia: ANC <500
Most inpatient treatment guidelines quantify clinical neutropenia as an ANC <500 or 500–1000 with an anticipated fall to <500.
The risk of invasive infection increases with the degree of neutropenia, with 20–50% of patients with an ANC <100 developing bacteremia.
Physical examination should be complete to localize possible sources of infection, and include the mouth and pharynx, back, anogenital region, eyes, and any indwelling catheters.
Avoid rectal thermometer and digital rectal examination given the risk of bacterial translocation.
Laboratory investigations should include:
- Complete blood count with differential.
- Sputum cultures.
- Two sets of blood cultures (for patients with indwelling catheters take one blood culture from a peripheral site and one from the central catheter. A differential time to positivity analysis should be performed).
- Urinalysis and urine culture.
- Complete metabolic panel.
  - Cerebrospinal fluid (CSF) studies depending on clinical suspicion (CSF may be acellular despite active CNS infection and often shows a lymphocytic pleocytosis with normal protein and glucose levels).
  - Lactic acid if there is a concern for early sepsis.
Radiographic investigation should include:
- Chest radiograph (a good initial screening for active pulmonary process; however, high-resolution computed tomography (CT) may reveal evidence of pneumonia in half of febrile neutropenic patients with an unremarkable chest radiograph).
Ultrasound/CT/magnetic resonance imaging (MRI) can be ordered as needed.

Critical management

Immediate assessment of systemic compromise should guide initial management and resuscitation. Rapid collection of blood cultures followed by administration of antibiotics should be achieved within 30 minutes of presentation in the unstable patient, and within 1 hour in the stable patient.
Options for initial antibiotic selection are presented in Table 50.2.
In the stable patient, routinely adding vancomycin in the first 72 hours does not reduce mortality and increases nephrotoxicity. Indications for adding vancomycin to the antibiotic regimen are:
- Catheter-related infection
- Known colonization with methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant streptococci
- Blood cultures positive for Gram-positive bacteria and susceptibilities unknown
- Hypotension.
Initially starting antifungal or antiviral therapy is not recommended. However, a lower threshold for broadened initial therapy should be maintained in the critically ill, and based on medical history (prior use of antibiotics, steroids, etc.).
Current management guidelines of severe sepsis/septic shock (central line with early goal-directed therapy, ARDS network lung protective ventilation, and glycemic control) should be instituted in septic neutropenic patients.
Many neutropenic patients are concomitantly anemic. No clear optimal transfusion level is known and packed red blood cell administration should be guided by evidence of tissue perfusion.
There is currently insufficient evidence to support or refute the use of colony-stimulating factor. Most studies agree its use does not change immediate mortality.
Platelet transfusion guidelines are similar to other disease processes, frequently when less than 10 × 10⁹/L, or less than 50 × 10⁹/L if the patient is actively bleeding.
Patients with neutropenic fever at low risk for serious complications can potentially be managed as outpatients. Validated tools such as the Multinational Association for Supportive Care in Cancer Risk Index (MASCC risk score) can be used to help select appropriate candidates for discharge. These decisions are institution dependent, however, and should never be made without close discussion with a hematologist/oncologist consultant.