Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood. It is an oncologic emergency, and is the most common serious complication in patients with hematopoietic cancers or receiving chemotherapy for cancer. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well. In 50% of cases, an infection is detectable; bacteremia (bacteria in the bloodstream) is present in approximately 20% of all patients with this condition.
Definition Febrile neutropenia or neutropenic fever is a defined as a single oral temperature value of ≥ 38.3 C (101 F) or a temperature ≥ 38 C (100.4 F) for ≥ 1 hour, with an absolute neutrophil count (ANC) < 1500 cell/microliter. In case of severe neutropenia, the ANC is < 500 cell/microliter. In profoundly severe neutropenia, the ANC is < 100 cells/microliter.
Pathophysiology Febrile neutropenia can develop in any form of neutropenia, but is most generally recognized as a complication of chemotherapy when it is myelosuppressive (suppresses the bone marrow from producing blood cells). Febrile neutropenia is the most common and serious complication in patients with hematopoietic cancers or receiving chemotherapy for cancer. The condition occurs when a neutropenic patient gets infected by a pathogen. Approximately 50% of patients with febrile neutropenia develop an infection, of which 20% with profound neutropenia will develop bacteremia. Gram-positive bacteria are now the most common pathogens causing febrile neutropenia, with many of these infections resulting from long-term central venous catheters.
Etiology and antimicrobial susceptibility patterns In patients with solid tumors, febrile neutropenia (FN) has a clinically identifiable focus in approximately 65% of episodes. However, microbiological documentation is achieved in only 20–30% of cases, and blood cultures are positive in 10–25%.Carmona-Bayonas A, Jiménez-Fonseca P, de Castro EM, Mata E, Biosca M, Custodio A, et al. SEOM clinical practice guideline: management and prevention of febrile neutropenia in adults with solid tumors (2018). Clin Transl Oncol. 2019;21(1):75–86. doi:10.1007/s12094-018-1917-5 . The most frequent etiology is bacterial, involving both Gram-negative bacilli and Gram-positive cocci, with an approximate ratio of 3:2.Carmona-Bayonas A, Jiménez-Fonseca P, Virizuela J, Antonio M, Font C, Biosca M, et al. Performance of the Clinical Index of Stable Febrile Neutropenia (CISNE) in different types of infections and tumors. Clin Transl Oncol. 2017;19(3):386–395. doi:10.1007/s12094-016-1542-1 .Carmona-Bayonas A, Fonseca PJ, Font C, Martínez-García J, Torrella F, Urrego E, et al. Bacteremia in adult cancer patients with apparently stable febrile neutropenia: data from a cohort of 692 consecutive episodes from a single institution. J Community Support Oncol. 2014;12(9):312–320. PMID:25848908 .
The selective pressures that favor Gram-positive infections in hematologic patients—such as central venous catheters, fluoroquinolone prophylaxis, grade 3–4 mucositis, or viral infections—are generally less intense in patients with solid tumors. Anaerobic or polymicrobial infections are uncommon but may occur in special circumstances, such as abscesses or enteritis.
In recent years, infections caused by resistant strains, particularly extended-spectrum β-lactamase (ESBL)- or carbapenemase-producing bacteria, have increased.Trecarichi EM, Tumbarello M. Antimicrobial-resistant Gram-negative bacteria in febrile neutropenic patients with cancer: current epidemiology and clinical impact. Curr Opin Infect Dis. 2014;27(2):200–210. doi:10.1097/QCO.0000000000000046 . The risk of resistant microorganisms depends on previous colonization, invasive procedures, prior antibiotic exposure, recent hospitalization, chronic comorbidities, and local resistance patterns.Carmona-Bayonas A, Jiménez-Fonseca P, Virizuela J, Antonio M, Font C, Biosca M, et al. Performance of the Clinical Index of Stable Febrile Neutropenia (CISNE) in different types of infections and tumors. Clin Transl Oncol. 2017;19(3):386–395. doi:10.1007/s12094-016-1542-1 .Carmona-Bayonas A, Fonseca PJ, Font C, Martínez-García J, Torrella F, Urrego E, et al. Bacteremia in adult cancer patients with apparently stable febrile neutropenia: data from a cohort of 692 consecutive episodes from a single institution. J Community Support Oncol. 2014;12(9):312–320. PMID:25848908 .
According to European surveillance data, resistance rates reported in 2015 for Gram-positive pathogens were 10–25% to macrolides among pneumococci, 25–50% resistance to cloxacillin among Staphylococcus aureus, up to 90% in coagulase-negative staphylococci, and 1–5% vancomycin resistance in Enterococcus faecium.European Antimicrobial Resistance Surveillance Network (EARS-Net). Antimicrobial resistance surveillance in Europe 2015: Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). European Centre for Disease Prevention and Control, Stockholm, 2015. Available online .
Invasive fungal infections (IFIs) are uncommon in patients with solid tumors (<8%).Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016;27(Suppl 5):v111–v118. doi:10.1093/annonc/mdw325 . Risk factors for IFIs include prior antibiotic exposure, multiple lines of chemotherapy, prolonged corticosteroid use (≥20 mg/day prednisone equivalent for ≥4 weeks), extensive mucositis, central venous catheters, and prolonged neutropenia (>7 days). Candida albicans accounts for the majority of candidemia cases, though infections due to fluconazole-resistant species such as Candida krusei and Candida glabrata have become more frequent. Seasonal respiratory viruses are common in exposed contacts, but reactivation of latent viruses or those typically associated with acute leukemia or hematopoietic stem cell transplantation is rare among patients with solid tumors.
Diagnosis
Initial evaluation and risk stratification The main goals of the initial clinical assessment in febrile neutropenia (FN) are to determine the severity of illness, identify a potential infectious focus, and clarify the epidemiological context (for instance, recent antibiotic use or previous microbiological isolates). A thorough and systematic physical examination should be performed, focusing on likely sites of infection such as central venous catheters (CVC), skin and soft tissues, the perineal area, respiratory tract, oral cavity, pharynx, sinuses, and abdomen, as well as a neurological assessment and fundoscopy in patients with visual symptoms.
Before starting empirical antibiotics, two blood cultures should be obtained (at least one through the CVC if present), along with additional samples according to clinical suspicion (e.g., urine, sputum, mucosal or skin lesions, stool, cerebrospinal fluid, urinary antigens for pneumococcus and/or Legionella spp., or nasopharyngeal swabs for influenza virus during seasonal outbreaks). Laboratory studies should include a complete blood count, liver and renal function tests, lactate, and a chest X-ray in two projections. Procalcitonin (>0.5 ng/mL) is a more sensitive and early marker than C-reactive protein (≥90 mg/dL) for detecting bacteremia and predicting FN complications, although its incremental value beyond clinical criteria remains uncertain.
In patients with pulmonary infiltrates or profound immunosuppression (e.g., corticosteroids, prolonged neutropenia, immunosuppressive drugs), early bronchoscopy with bronchoalveolar lavage may be indicated. A complete microbiologic workup (viruses, fungi, atypical bacteria) is warranted in selected patients with compatible clinical or epidemiologic features. For patients with respiratory symptoms and an inconclusive chest X-ray, or with persistent fever ≥72 hours and risk factors for complications, chest computed tomography (CT) is more sensitive (87%) and has a negative predictive value of 88%, outperforming plain radiography. Abdominal X-rays have low sensitivity and specificity, and abdominal CT should be preferred when an intra-abdominal source (e.g., enterocolitis, typhlitis) is suspected.
Severity should be assessed clinically before applying prognostic scores. Most patients with solid tumors and FN (approximately 3:1) appear clinically stable during the first three hours after diagnosis.Carmona-Bayonas A, Gómez J, González-Billalabeitia E, Canteras M, Navarrete A, Gonzálvez ML, et al. Prognostic evaluation of febrile neutropenia in apparently stable adult cancer patients. Br J Cancer. 2011;105(5):612–617. doi:[10.1038/bjc.2011.293](https://doi.org/10.1038/bjc.2011.293).Carmona-Bayonas A, Jiménez-Fonseca P, Echaburu JV, Antonio M, Font C, Biosca M, et al. Prediction of serious complications in patients with seemingly stable febrile neutropenia: validation of the Clinical Index of Stable Febrile Neutropenia in a prospective cohort of patients from the FINITE study. J Clin Oncol. 2015;33(5):465–471. doi:[10.1200/JCO.2014.58.7991](https://doi.org/10.1200/JCO.2014.58.7991).
High-risk or potentially unstable patients include those with sepsis (defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, reflected by an increase of ≥2 points in the SOFA score), septic shock, or severe documented infections such as pneumonia, empyema, peritonitis, cellulitis (>4.5 cm), typhlitis, grade 3–4 enteritis, appendicitis, cholecystitis, meningitis, encephalitis, catheter-related infection, endocarditis, or pyelonephritis.Taplitz RA, Kennedy EB, Flowers CR, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: ASCO and IDSA clinical practice guideline update summary. J Oncol Pract. 2018;14(4):250–254. doi:[10.1200/JOP.17.00023](https://doi.org/10.1200/JOP.17.00023). In such cases, mortality from sepsis may reach 18.1%, compared with 2.7% among low-risk patients. The infections associated with the highest mortality include pneumonia, bacteremia (especially due to Gram-negative bacilli), and invasive fungal infections. Tumor progression and lung cancer are also associated with poorer prognosis. Additional comorbidities such as mucositis, enteritis, thrombocytopenia, thromboembolic disease, or transfusion requirements further influence clinical decisions.Carmona-Bayonas A, Jiménez-Fonseca P, Echaburu JV, Antonio M, Font C, Biosca M, et al. J Clin Oncol. 2015;33(5):465–471.
The following table lists common high-risk clinical features that contraindicate outpatient management of FN:
Table 1. High-risk clinical factors that contraindicate outpatient management of febrile neutropenia System or organ Risk factors Vascular Syncope, systolic blood pressure <90 mmHg, hypertensive crisis, arrhythmias, heart failure, clinically relevant bleeding, angina pectoris Hematologic Other clinically relevant cytopenias (platelets <50,000/μL, hemoglobin <8 g/dL), thromboembolic disease Gastrointestinal Oral intolerance, vomiting, diarrhea, abdominal pain, jaundice, altered liver function tests Infectious Sepsis or severe focus (pneumonia, extensive cellulitis, bacteremia, catheter infection, pyelonephritis, meningitis, cholecystitis or other surgical infections), antibiotic allergy, recent antibiotic use Neurological Focal neurological symptoms, suspected meningitis, acute confusional state Pulmonary Abscesses, pneumothorax, pleural effusion, acute respiratory failure, pulmonary infiltrates or cavitated nodules Other Acute renal failure, dehydration, delirium, electrolyte imbalance, other severe complications, pregnancy, fractures