Approach
Febrile neutropenia is an oncological emergency and early recognition of patients at risk for febrile neutropenia is vital.
Early recognition and diagnosis 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.[7]
Identifying the chemotherapy regimen (and when it was last administered) is crucial to confirming a diagnosis of febrile neutropenia, and to initiating a rapid evaluation so that antibiotics can be administered promptly.
History should document factors associated with increased risk of febrile neutropenia, including the following (see Risk factors for more detail):[3][7][8][9][10][11][21][22][23][25][26][27][28][30][31][32]
Age >65 years
Haematological malignancy (approximately 5-fold increased incidence of febrile neutropenia compared with patients treated for solid tumour or lymphoma)
Pre-existing organ dysfunction (e.g., heart, liver, and/or kidney disease) and comorbid conditions
Recent chemotherapy (particularly full-dose intensity)
Chemoradiotherapy
First-cycle nadir absolute neutrophil count (ANC) (<500 cells/microlitre)
Immunosuppressive therapy (e.g., high-dose corticosteroids, rituximab, alemtuzumab)
Prior chemotherapy-induced neutropenia
Female sex
Eastern Cooperative Oncology Group performance status (ECOG PS) >1.
Screen for epidemiological 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, respectively]; recent blood transfusions) and other exposures (e.g., ill contacts; pets), as these may offer a clue to possible infection and help establish the cause of febrile neutropenia.
Drug allergies may influence the choice of empirical antibiotics and should also be part of the history enquiry.
Clinical examination
Fever may be the only sign of infection in neutropenic patients, due to an inability to mount an adequate inflammatory response.
Heart rate and blood pressure should be carefully monitored.
Neutropenic patients with indwelling catheters are at risk for catheter-related infections, including bloodstream infection and tunnel tract 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 febrile neutropenic patient should include a thorough physical examination.
Sinuses: paranasal sinuses are a frequent site of occult infection in patients with neutropenia. Patients with sinusitis may present with sinus tenderness.
Chest: an examination 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: infections should be evaluated by careful examination of the entire skin, 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, or discharge.
Abdomen: gastrointestinal tract infections may manifest with abdominal pain, nausea or vomiting, and/or diarrhoea. Patients with neutropenia are at increased risk of infection anywhere along the gastrointestinal tract (e.g., oesophagitis, enterocolitis).
Perianal region: gentle perirectal inspection is considered important to evaluate for perirectal abscess or other abnormalities, particularly in patients with localising complaints.
Oral cavity/oropharynx: examination may reveal inflammation or frank ulceration.
Absence of fever does not exclude infection in patients with neutropenia, and may be a poor prognostic feature.[48] 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
Full blood count (FBC) with differential, urea, creatinine, liver function tests (LFTs), and peripheral and/or central venous catheter blood cultures should be ordered immediately for any patient presenting with fever or other signs and symptoms of infection, who has recently received chemotherapy.
Urine culture and stool studies should be obtained, and lumbar puncture performed, if and when clinically indicated.
FBC and differential
Febrile neutropenia is defined as a single oral temperature measurement of >38.3ºC (>101ºF) or a temperature of ≥38.0ºC (≥100.4ºF) sustained over 1 hour, with an ANC of <500 cells/microlitre, or an ANC that is expected to decrease to <500 cells/microlitre over the next 48 hours.[1]
Urinalysis and renal function tests (including urea and creatinine)
Evidence of kidney dysfunction has been associated with increased risk of complications from neutropenia.[3][25] Patients with abnormal renal function are not suitable for outpatient therapy.
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 (<35 g/L [<3.5 g/dL]), elevated bilirubin, and elevated liver enzymes (aspartate aminotransferase and alkaline phosphatase) in patients receiving chemotherapy for cancer are independent risk factors for febrile neutropenia, and complications related to febrile neutropenia.[9][22][23][24]
Blood cultures
Blood cultures should be obtained promptly from all patients with neutropenia who present with fever or report fever.
At least two sets of blood cultures should be obtained from separate sites/draws, followed by initiation of empiric antibiotics.
If fever persists after empirical antibiotics have been started, and assuming blood cultures are negative, then repeat blood cultures should be obtained on the next 2 days.[1] Continuing blood cultures after this time is not usually required, unless prompted by a clinical change.
Urine culture
Urinary tract infection is relatively common in patients with febrile neutropenia, but pyuria is likely to be absent in most cases, owing to leukopenia.[49][50]
Urine culture should be obtained to identify the presence of a pathogen if a patient has urinary tract symptoms (results should be interpreted cautiously if a urinary catheter is present).
Gastrointestinal pathogen molecular assay
Clostridioides difficile-associated disease is a common cause of colitis 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.[51] These assays can provide rapid results with high sensitivity and specificity.[52]
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 febrile neutropenia who demonstrate signs or symptoms possibly attributable to central nervous system (CNS) infection (e.g., headache, neck stiffness, photophobia, altered mental status, and/or lethargy).
CT head scan or other CNS imaging must be obtained prior to lumbar puncture in patients with febrile neutropenia to ensure that it is safe to proceed.
Fungal assays
For patients who remain neutropenic and persistently febrile following 3 to 5 days of empirical antibiotics, non-bacterial infections (e.g., fungal infection, viral infection) and non-infectious causes of fever (e.g., drug fever, tumour fever) should be considered.
For these patients (and any patient at increased risk for invasive fungal infection) serological evaluation for Aspergillus and other fungi infection using the galactomannan assay and 1,3-beta-D-glucan, respectively, can be considered.
Chest and sinus imaging (preferably with CT) should also be considered as these are relevant sites of involvement with invasive mould infection in patients with neutropenia.
Viral assays
Viral molecular assays (e.g., PCR) should be performed if viral infections are suspected based on history and possible exposures.
Multiplex PCR assays are typically used in the diagnostics work-up 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 the chest x-ray is unrevealing and there is concern for respiratory tract infection and/or persistent fever despite 3 to 5 days of empirical guideline concordant antibiotics, or if findings on chest x-ray warrant further delineation.[53]
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 bacteraemia to assess for infective endocarditis and possible complications.[54] It should also be considered in patients with suspected infective endocarditis, including those with persistent high-grade bacteraemia due to other gram-positive bacteria (e.g., enterococci or viridans group streptococci), Candida species, and occasionally gram-negative rods.
It is reasonable to start with a trans-thoracic echocardiogram (TTE), and to consider a trans-oesophageal echocardiogram in patients for whom the TTE is non-diagnostic and the index of suspicion for infective endocarditis is moderate or high.
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