Approach
Febrile neutropenia is an oncologic emergency and early recognition of patients at risk for febrile neutropenia is vital.
Early recognition, diagnostic evaluation, and management of febrile neutropenia requires a thorough history and physical examination.
History
Patients who have recently received chemotherapy, particularly at full-dose intensity, are at risk for febrile neutropenia.[12]
History should document factors associated with increased risk of febrile neutropenia, including the following (see Risk factors for more detail):
Age >65 years
Hematologic malignancy (increased risk compared with solid tumor)
Low albumin (<3.5 g/dL)
Elevated bilirubin
Elevated liver enzymes
Preexisting organ dysfunction (e.g., heart, liver, and/or kidney disease) and comorbid conditions
Recent chemotherapy (particularly full-dose intensity)
Chemoradiation therapy
First-cycle nadir absolute neutrophil count (<500 cells/microliter)
Prior chemotherapy-induced neutropenia
Persistent neutropenia ≥7 days
Bone marrow involvement
Recent surgery
Immunosuppressive therapy (e.g., high-dose corticosteroids, rituximab, alemtuzumab)
Advanced disease stage
Female sex
Eastern Cooperative Oncology Group performance status (ECOG PS) >1
The history should also include prior significant infections, recent antibiotic therapy or antimicrobial prophylaxis, and use of invasive devices (e.g., catheter).[4]
Screen for epidemiologic exposures and historical features (e.g., recent or prior travel, particularly to regions where tuberculosis or endemic fungi are prevalent in the population or environment) and other exposures (e.g., ill contacts; pets; environmental exposures associated with increased risk for mold or waterborne infection), as these may offer a clue to possible infection and help establish the cause of febrile neutropenia.
Drug allergies may influence the choice of empiric antibiotics and should also be part of the history enquiry.
Clinical exam
Fever may be the only sign of infection in patients with neutropenia, due to a decreased ability to mount an adequate inflammatory response.
Patients with neutropenia with indwelling catheters are at risk for catheter-related infections, including bloodstream infection and tunnel or site infection. Inflammation or frank ulceration of the lining of the mouth, as well as infection, inflammation, or ulceration of the lining of the genital or anal mucosa, can be a portal of entry for endogenous flora into the bloodstream.
Evaluation of any patient with febrile neutropenia should include a thorough physical exam.
Sinuses: paranasal sinuses are a frequent site of occult infection (both bacterial and fungal) in patients with neutropenia. Patients with sinusitis may present with sinus tenderness, nasal congestion, and/or headache.
Chest: an exam should be carried out in patients at initial presentation with neutropenic fever; pneumonia is common in patients with febrile neutropenia, but cough, abnormal breath sounds, and shortness of breath may be absent owing to a decreased immune response.
Skin/soft tissue: careful examination of the entire skin surface should be conducted, including skin folds, bodily orifices, catheter insertion sites, and prior biopsy sites/wounds. Catheter insertion sites, current or prior, should be examined for signs of infection such as erythema, induration, discharge, and/or local tenderness.
Abdomen: gastrointestinal tract infections may manifest with abdominal pain, nausea or vomiting, and/or diarrhea. Patients with neutropenia are at increased risk of infection anywhere along the gastrointestinal tract (e.g., esophagitis, enterocolitis).
Perianal region: gentle perirectal inspection is considered important to evaluate for perirectal abscess or other abnormalities, particularly in patients with localizing complaints.
Oral cavity/oropharynx: exam may reveal inflammation or frank ulceration.
Absence of fever does not exclude infection in patients with neutropenia.[72] Patients may occasionally present without fever (particularly if they are receiving corticosteroids), but have other signs and symptoms suggestive of infection (e.g., hypotension, tachycardia).
Laboratory investigations
Complete blood count (CBC) with differential, blood urea nitrogen (BUN), creatinine, liver function tests (LFTs), and blood cultures should be ordered immediately for any patient who has recently received chemotherapy and presents with fever or other signs and symptoms of infection.
If indicated, urine and stool studies should be obtained, and lumbar puncture performed. In the absence of signs or symptoms of urinary tract infection (UTI), routine urine culture is unlikely to change management in patients with neutropenic fever and is not advised.[73][74]
CBC and differential
Febrile neutropenia is defined as a single oral temperature measurement of ≥101ºF (≥38.3ºC) or a temperature of ≥100.4ºF (≥38.0ºC) sustained over 1 hour, with an ANC of ≤500 cells/microliter, or an ANC of ≤1000 cells/microlitre that is expected to decrease to ≤500 cells/microliter over the next 48 hours.[3][4]
Renal function tests (including BUN and creatinine)
Evidence of kidney dysfunction has been associated with increased risk of complications from neutropenia.[6][48]
LFTs
Abnormal LFTs could indicate hepatobiliary infection, but may also occur in the setting of chemotherapy or other drug-related toxicity, or progressive disease with liver involvement.
Low albumin (<3.5 g/dL), elevated bilirubin, and elevated liver enzymes (aspartate aminotransferase and alkaline phosphatase) in patients receiving chemotherapy for cancer are risk factors for febrile neutropenia, and complications related to febrile neutropenia.[13][35][37][38][39][40][41]
Blood cultures
At least two sets of blood cultures should be obtained from separate sites/draws (including at least one set from a peripheral site) before initiation of empiric antibiotics.[4] Results from the peripheral site culture can help to clarify whether a positive central venous catheter culture represents true bacteremia or a contaminated sample (false-positive). Some centers may use only peripheral cultures, given the potential for false-positive results with blood cultures obtained from a central venous catheter.[75]
If fever persists after empiric antibiotics have been started, and assuming blood cultures are negative, then repeat blood cultures should be obtained on each of the next 2 days.[3][76] Continuing blood cultures after this time is not typically recommended (unless there is a clinical change in the patient).
Urinalysis and urine culture
Only patients with signs or symptoms of UTI (e.g., dysuria, urinary frequency, pelvic or flank pain) should undergo urine sampling to evaluate for UTI.[20][73][74]
Dipstick urinalysis has a high negative predictive value in patients with cancer, including those with neutropenia.[77] Urinalysis with reflex urine culture is an appropriate diagnostic strategy for patients with neutropenia who have signs and/or symptoms of UTI.
Results of urine testing should be interpreted cautiously if a urinary catheter is present.[4]
Gastrointestinal pathogen molecular assay
Clostridioides difficile-associated disease is a common cause of diarrhea in patients with febrile neutropenia, in the context of frequent use of broad-spectrum antibiotics and extensive contact with the healthcare environment.
Stool evaluation can be carried out to identify the presence of C difficile or other gastrointestinal pathogens, if and when suspicion arises. Multiplex polymerase chain reaction (PCR)-based assays for gastrointestinal pathogens are increasingly preferred to stool culture.[78] These assays can provide rapid results with high sensitivity and specificity.[79]
Neutropenic enterocolitis (typhlitis), an acute inflammatory disorder of the intestinal tract (generally in the ileocecal region) should be evaluated with imaging studies (e.g., computed tomography [CT]).
Lumbar puncture
A lumbar puncture should be considered for patients with signs or symptoms of central nervous system (CNS) infection (e.g., headache, neck stiffness, photophobia, altered mental status, and/or lethargy).[4]
CNS imaging (e.g., head MRI or CT) must be obtained prior to lumbar puncture to ensure that it is safe to proceed.[4]
Consultation with infectious disease and neurology specialists is strongly recommended if CNS infection is suspected.[4]
Fungal tests
Fungal serology is indicated for any patient at risk for invasive fungal infection (e.g., neutropenia >10 days, prolonged use of high-dose systemic corticosteroid, hematopoietic cell transplantation recipient).[4] Evaluation includes the galactomannan assay (specific for invasive aspergillosis) and 1,3-beta-D-glucan assay (for aspergillosis and other invasive fungal infections).
For patients who remain neutropenic and persistently febrile following 3-5 days of empiric antibiotics, consider:[80]
Nonbacterial infections (e.g., fungal infection, viral infection) and noninfectious causes of fever (e.g., drug fever, tumor fever)
Serologic evaluation for Aspergillus and other fungi infection using the galactomannan assay and 1,3-beta-D-glucan assay
Chest and sinus imaging (preferably with CT) should also be considered as these are relevant sites of involvement with invasive mold infection in patients with neutropenia.
Viral assays
Viral molecular assays (e.g., PCR) should be performed if viral infection is suspected based on history and possible exposures.
Multiplex PCR assays are typically used in the diagnostic workup for patients who present with signs or symptoms suggesting a specific type of infection. For example, respiratory multiplex panel testing may be considered for patients presenting with signs or symptoms suggesting a respiratory viral infection (e.g., cough, shortness of breath).
Imaging
Patients with febrile neutropenia can have pneumonia without cough or abnormal breath sounds; therefore, a plain film chest x-ray should be obtained with the initial fever evaluation in all patients.
Chest CT imaging is more sensitive than chest x-ray and should be considered if:[81]
the chest x-ray is unrevealing and there is concern for respiratory tract infection and/or persistent fever despite 3-5 days of empiric guideline concordant antibiotics; or
chest x-ray findings warrant further delineation.
CT imaging of the abdomen and pelvis should be performed if there are signs or symptoms suggestive of intra-abdominal infection (e.g., abscess, perforation, colitis) or biliary tract process.
Echocardiogram
An echocardiogram should be ordered in all patients with Staphylococcus aureus bacteremia to assess for infective endocarditis and possible complications.[82]
Echocardiogram should also be considered in patients with suspected infective endocarditis, including those with persistent high-grade bacteremia due to other gram-positive bacteria (e.g., enterococci or viridans group streptococci), Candida species, and occasionally gram-negative rods.[83]
It is reasonable to start with a transthoracic echocardiogram (TTE), and to consider a transesophageal echocardiogram in patients for whom the TTE is nondiagnostic and the index of suspicion for infective endocarditis is moderate or high.[83]
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