Investigations
1st investigations to order
FBC and differential
Test
Should be ordered immediately for any patient who has recently received chemotherapy and presents with fever or other signs and symptoms of infection.
Result
absolute neutrophil count (ANC) ≤500 cells/microlitre (or ≤1000 cells/microlitre and expected to decrease to ≤500 cells/microlitre over the next 48 hours)
renal function tests (urea and creatinine)
Test
Should be ordered immediately for any patient who has recently received chemotherapy and presents with fever or other signs and symptoms of infection.
Evidence of kidney dysfunction has been associated with increased risk of complications from neutropenia.[6][48]
Result
normal or elevated urea and creatinine
liver function tests (LFTs)
Test
Should be ordered for any patient who has recently received chemotherapy and presents with fever or other signs and symptoms of infection.
Abnormal LFTs could indicate a 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 risk factors for febrile neutropenia and complications related to febrile neutropenia.[13][35][37][38][39][40][41]
Result
abnormal LFTs (low albumin [<35 g/L (<3.5 g/dL)]; elevated bilirubin; elevated aspartate aminotransferase; elevated alkaline phosphatase)
blood cultures
Test
Should be ordered for any patient who has recently received chemotherapy and presents with fever or other signs and symptoms of infection.
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 empirical antibiotics.[4] Results from the peripheral site culture can help to clarify whether a positive central venous catheter culture represents true bacteraemia or a contaminated sample (false-positive). Some centres 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 empirical 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).
Result
may be positive for a pathogen
chest x-ray
Test
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.
Result
may identify pulmonary infiltrates
Investigations to consider
gastrointestinal pathogen molecular assay
Test
Clostridioides difficile-associated disease is a common cause of diarrhoea 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., CT scan).
Result
positive for pathogen in gastrointestinal infection
urinalysis and urine culture
Test
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 urinary tract infection (UTI).
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]
Results of urine testing should be interpreted cautiously if a urinary catheter is present.[4]
Result
positive for a pathogen in urinary tract infection
lumbar puncture
Test
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]
Result
elevated cerebrospinal fluid (CSF) opening pressure, protein, white or red blood cells; low CSF glucose in CNS infection
fungal test
Test
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, haematopoietic 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 empirical antibiotics, consider: non-bacterial infections (e.g., fungal infection, viral infection) and non-infectious causes of fever (e.g., drug fever, tumour fever); and serological evaluation for Aspergillus and other fungi infection using the galactomannan assay and 1,3-beta-D-glucan assay.[80]
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.
Result
positive for a fungal organism in fungal infection
viral molecular assay
Test
Viral molecular assays (e.g., polymerase chain reaction [PCR]) should be performed if viral infection is suspected based on history and possible exposures.
Multiplex PCR assays are typically used in the diagnostic 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).
Result
positive for a virus in viral infection
echocardiogram
Test
An echocardiogram should be ordered in all patients with Staphylococcus aureus bacteraemia 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 bacteraemia 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 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.[83]
Result
sonographic evidence of a valvular vegetation by either trans-thoracic or trans-oesophageal echocardiogram
CT scans of the chest, abdomen, and pelvis
Test
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 3-5 days of empirical guideline concordant antibiotics; or chest x-ray findings warrant further delineation.[81]
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.
Result
pulmonary infiltrates on CT scan of the chest in pneumonia; an abscess on CT scan of the chest, abdomen, or pelvis; inflammation or obstruction of the intestines, gall bladder, pancreas and biliary tree, and genito-urinary tract
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