History and exam
Key diagnostic factors
common
recent chemotherapy
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.
fever
Patients receiving chemotherapy who report a prior or current febrile episode should be evaluated quickly for neutropenia with blood cultures so that antibiotics can be administered promptly.
Febrile neutropenia is defined as a single oral temperature measurement of >101°F (>38.3ºC) or a temperature of ≥100.4ºF (≥38.0ºC) sustained over 1 hour, with an absolute neutrophil count (ANC) of <500 cells/microliter, or an ANC that is expected to decrease to <500 cells/microliter over the next 48 hours.[1]
Other diagnostic factors
common
age >65 years
immunosuppressive therapy
Patients treated with profoundly immunosuppressive regimens (e.g., containing high-dose corticosteroids, rituximab, alemtuzumab, or other agents that can cause immediate and delayed impairment of cellular immunity) are at risk for febrile neutropenia.[30][31]
A retrospective study of 15,971 adult patients with non-Hodgkin lymphoma or breast, lung, colorectal, ovarian, or gastric cancer found that oral corticosteroid use within 3 months prior to chemotherapy initiation was associated with a significant increase in risk for febrile neutropenia (adjusted hazard ratio 1.53, 95% CI 1.17 to 1.98).[32]
prior chemotherapy-induced neutropenia
Prior chemotherapy-induced neutropenia is a risk factor for recurrent neutropenia and neutropenic fever.[26]
low performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] >1)
Patients with worse ECOG PS are at increased risk of febrile neutropenia during chemotherapy.
In a large prospective study of patients receiving chemotherapy for solid tumors or lymphoma, an ECOG PS ≥1 was associated with an increased risk of febrile neutropenia.[8]
If performance status is good, it may help to stratify patients who are candidates for outpatient therapy.
hematologic malignancies
Patients being treated for hematologic malignancies have an approximately fivefold increased incidence of developing febrile neutropenia compared with patients being treated for solid tumors.[11]
advanced-stage disease
prior antibiotic regimens
Patients who have received antibiotics for previous episodes of chemotherapy-induced neutropenia are at increased risk for fungal infections, Clostridioides difficile infections, and infections with multidrug resistant organisms (e.g., vancomycin-resistant enterococci, extended-spectrum beta-lactamase [ESBL] producers, and carbapenem-resistant Enterobacterales).
low albumin (<3.5 g/dL)
An albumin level <3.5 g/dL in patients receiving chemotherapy for cancer, perhaps indicating a poor nutritional status, is associated with an increased risk for febrile neutropenia and complications related to febrile neutropenia.[9][22][23]
A study of 240 patients with non-Hodgkin lymphoma identified a low baseline albumin (<3.5 g/dL) as a risk factor for febrile neutropenia following the first cycle of chemotherapy.[9]
elevated bilirubin and liver enzymes (aspartate aminotransferase and alkaline phosphatase)
pre-existing organ dysfunction and comorbid conditions
Patients with pre-existing heart, liver, and/or kidney disease are at increased risk of developing febrile neutropenia during chemotherapy, and complications related to febrile neutropenia.[3][7][10][25]
Having ≥1 comorbid condition (e.g., congestive heart failure, myocardial infarction, peripheral vascular disease, cerebrovascular disease, diabetes, renal disease, liver disease, connective tissue disease) has been identified as a risk factor for febrile neutropenia in patients receiving chemotherapy for solid tumors and lymphoma.[8][10]
low first-cycle nadir absolute neutrophil count (<500 cells/microliter)
Patients with a low nadir absolute neutrophil count (i.e., <500 cells/microliter) following the first cycle of chemotherapy are at risk of developing febrile neutropenia with subsequent cycles of chemotherapy.[26]
signs of pneumonia (cough, abnormal breath sounds, shortness of breath)
Pneumonia is common in patients with febrile neutropenia.
Many patients with febrile neutropenia have pneumonia without cough, abnormal breath sounds, or shortness of breath due to a decreased immune response.
abdominal pain
Patients with neutropenia are at increased risk of infection anywhere along the gastrointestinal tract (e.g., esophagitis, enterocolitis).
Gastrointestinal tract infections may manifest with abdominal pain, nausea or vomiting, and/or diarrhea.
nausea or vomiting
Patients with neutropenia are at increased risk of infection anywhere along the gastrointestinal tract (e.g., esophagitis, enterocolitis).
Gastrointestinal tract infections may manifest with abdominal pain, nausea or vomiting, and/or diarrhea.
diarrhea
Patients with neutropenia are at increased risk of infection anywhere along the gastrointestinal tract (e.g., esophagitis, enterocolitis).
Gastrointestinal tract infections may manifest with abdominal pain, nausea or vomiting, and/or diarrhea.
skin erythema, warmth, tenderness
Patients with neutropenia are at increased risk for skin or soft-tissue infection, including at sites of catheterization and prior biopsy.
Careful examination of the entire skin, including skin folds, bodily orifices, catheter insertion sites, and prior biopsy sites/wounds, is warranted.
mucositis or oral ulcers
Inflammation or frank ulceration of the lining of the mouth can be a portal of entry for endogenous flora into the bloodstream.
infection, inflammation, or ulceration of genital and anal area
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.
Gentle perirectal inspection is now considered important to evaluate for perirectal abscess or other abnormalities, particularly in patients with localizing complaints.
infected indwelling catheters
Neutropenic patients with indwelling catheters are at risk for catheter-related infections, including bloodstream infection and/or tunnel tract infection.
All catheters and sites, current or prior, should be examined for signs of infection such as erythema, induration, or discharge.
uncommon
pyuria
chemoradiation therapy
Patients treated with combined chemotherapy and radiation therapy (chemoradiation therapy) have an increased risk of febrile neutropenia.[26]
recent historical features and exposures
It is important to 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, 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.
sinus tenderness
The paranasal sinuses are a frequent site of occult infection (both bacterial and fungal) in neutropenic patients. Patients with sinusitis may present with sinus tenderness.
Risk factors
strong
age >65 years
hematologic malignancies
Patients being treated for hematologic malignancies have an approximately fivefold increased incidence of febrile neutropenia compared with patients treated for solid tumors.[11]
low albumin (<3.5 g/dL)
An albumin level <3.5 g/dL, perhaps indicating a poor nutritional status, is associated with an increased risk for febrile neutropenia and complications related to febrile neutropenia.[9][22][23]
One study of 240 patients with non-Hodgkin lymphoma identified a low baseline albumin (<3.5 g/dL) as a risk factor for febrile neutropenia following the first cycle of chemotherapy.[9]
elevated bilirubin
elevated liver enzymes
pre-existing organ dysfunction and comorbid conditions
Patients with pre-existing heart, liver, and/or kidney disease are at increased risk of developing febrile neutropenia during chemotherapy, and complications related to febrile neutropenia.[3][7][10][25]
Having ≥1 comorbid condition (e.g., congestive heart failure, myocardial infarction, peripheral vascular disease, cerebrovascular disease, diabetes, renal disease, liver disease, connective tissue disease) has been identified as a risk factor for febrile neutropenia in patients receiving chemotherapy for solid tumors and lymphoma.[8][10]
recent chemotherapy
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.
low first-cycle nadir absolute neutrophil count (<500 cells/microliter)
Patients with a low nadir absolute neutrophil count (i.e., <500 cells/microliter) following the first cycle of chemotherapy are at risk of developing febrile neutropenia with subsequent cycles of chemotherapy.[26]
chemoradiation therapy
Patients treated with combined chemotherapy and radiation therapy (chemoradiation therapy) have an increased risk of febrile neutropenia.[26]
prior chemotherapy-induced neutropenia
A history of previous chemotherapy-induced neutropenia is a risk factor for recurrent neutropenia and neutropenic fever.[26]
Patients who have received antibiotics for previous episodes of chemotherapy-induced neutropenia are at increased risk for fungal infection, Clostridioides difficile infection, and infections with multidrug resistant organisms (e.g., vancomycin-resistant enterococci, extended-spectrum beta-lactamase [ESBL] producers, and carbapenem-resistant Enterobacterales).
weak
female sex
low performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] >1)
Patients with worse ECOG PS are at increased risk of febrile neutropenia during chemotherapy.
In a large prospective study of patients receiving chemotherapy for solid tumors or lymphoma, an ECOG PS >1 was associated with an increased risk of febrile neutropenia.[8]
advanced-stage disease
immunosuppressive therapy
Patients treated with profoundly immunosuppressive regimens (e.g., containing high-dose corticosteroids, rituximab, alemtuzumab, or other agents that can cause immediate and delayed impairment of cellular immunity) are at risk for febrile neutropenia.[30][31]
A retrospective study of 15,971 adult patients with non-Hodgkin lymphoma or breast, lung, colorectal, ovarian, or gastric cancer found that oral corticosteroid use within 3 months prior to chemotherapy initiation was associated with a significant increase in risk for febrile neutropenia (adjusted hazard ratio 1.53, 95% CI 1.17 to 1.98).[32]
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