Neutropenic fever is when there is a single oral temperature of greater than or equal to 101 F, or a temperature greater than or equal to 100.4 F for at least an hour, with an absolute neutrophilic count (ANC) of less than 1500 cells/microliter. In severe neutropenia, the ANC is less than 500 per microliter or ANC that is expected to decrease below 500 cells/microL in the next 2 hours. In profound neutropenia, the ANC is less than 100 cells/microliter. To calculate ANC, multiply the total white blood cell (WBC) count by the percentage of polymorphonuclear cells (PMNs) and band neutrophils.
In the majority of cases, the infectious etiology is unable to be determined and gets marked as a fever of unknown origin (FUO). The definition of FUO is neutropenic cases with a fever greater than 38.3 C, without any clinically or microbiologically defined infection. Documented infections only comprise approximately 30% of cases. However, infections are the primary cause of morbidity and mortality in patients with cancer who present with fever and neutropenia. The majority of infections are bacterial, but viral or fungal etiology is possible. Common bacterial pathogens include gram-positive bacteria infections such as Staphylococcus, Streptococcus, and Enterococcus species. Drug-resistant organisms, including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species, have also been identified as infectious agents.
The specific frequency of agranulocytosis is unknown; It could be estimated to be 1.0 to 3.4 cases per million population per year. Neutropenia was particularly associated with HIV infection, acute leukemias, and myelodysplastic syndromes. Drug-induced neutropenia has an incidence of one case per million persons per year. About 50% of patients with febrile neutropenia will develop an infection, of which 20% with profound neutropenia will observe bacteremia.
Neutropenic fever is the most common and serious complication associated with hematopoietic cancers or with patients receiving chemotherapeutic regimens for cancer. Neutropenic fever occurs when a neutropenic patient encounters an infectious pathogen. In this immunocompromised state, patients lose or have weakened immunity to fend off infections. The host barriers, such as the mucosal lining of the GI tract or sinuses, may be damaged, leading the host, open to invasion from an infectious pathogen. About 1% of patients undergoing chemotherapy and radiation experience this complication.
A detailed history of the patients presenting illness, chemotherapy treatment, medication use, previous history of infections, especially with bacterial resistant organisms, and the presence of allergies, should be noted to guide your therapy. Signs of infection may require assessment; Pain and tenderness may be the only indicators of infection. Significant risk factors for the development of febrile neutropenia include older age, comorbidities, the specific type of cancer, and the type and number of myelosuppressive chemotherapy agents in use.
Lab tests should be ordered; complete blood count to determine the patient's neutropenic level; blood, urinalysis, and throat cultures are needed to determine the source of infection. Two sets of blood cultures should be obtained from a peripheral vein and any venous catheters as well as specimens for testing from any sites of infection, before the immediate administration of empirical broad-spectrum antimicrobial therapy. Urinary tract infections should be suspected in asymptomatic patients with a history of such infections. If diarrhea is present, a sample may be checked. If the patients have any respiratory symptoms, a chest x-ray is necessary.
Two widely used assessment tools, The Multinational Association for Supportive Care in Cancer (MASCC) and The Clinical Index of the Stable Febrile Neutropenia (CISNE), can be part of the patient interview. These tools can help to risk-stratify patients into high risk and low-risk neutropenic fever.
The MASCC was created the assess the risk of serious complications in patients with neutropenic fever. The MAASC index has a max score of 26. Patients with a score greater than 21 are considered low risk, and patients less than 21 are high risk.
MASCC Scoring Index
Type of Cancer
A more specific scale for classification of low-risk patients is the CISNE and may be more useful in the emergency department setting. One of the components of the scale is the Eastern Cooperative Oncology Group (ECOG) Performance Status, which helps determines the patient’s functional status as a surrogate for the patient’s ability to undergo therapies in serious illnesses.
The Clinical Index of Stable Febrile Neutropenia Score
In low-risk patients, oral empiric therapy with a fluoroquinolone plus amoxicillin/clavulanate is recommended in the outpatient setting. Clindamycin can be used for those with penicillin allergy. If the patient remains febrile for 48 to 72 hours, the patient will require admission.
For high-risk patients presenting with neutropenic fever, an intravenous antibiotic therapy should be given within 1 hour after triage and be monitored more than 4 hours before discharge. The Infectious Disease Society of America (IDSA) recommends monotherapy with antipseudomonal beta-lactam agents such as cefepime, carbapenems, or piperacillin and tazobactam.  Vancomycin is not recommended for initial therapy but should be considered if suspecting catheter-related infection, skin or soft tissue infections pneumonia, or hemodynamic instability. If patients do not respond to treatments, coverage should be expanded to include resistant species:
Recommendation for prevention of infection in neutropenic patients:
In the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that patients that are at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).
Febrile neutropenia is an oncological emergency that requires a team of infectious disease specialists, emergency medicine, oncology, pharmacy, and specialty-trained nurses and pharmacists for proper management, working as a collaborative interprofessional team. [Level 5] The most important determining factor of the outcomes of patients is the timing of administrating IV antibiotics. Early admission of antibiotics has been shown to reduce mortality and the hospital length of these patients. [Level 3] A heightened sense of urgency should be present in all staff members when interviewing with patients undergoing chemotherapy presenting with new-onset fever. The pharmacist should assist the team with antibiotic selection and dosing. The nursing staff should provide monitor of the patient and report untoward changes to the team. The best outcomes are achieved by an interprofessional team approach to the diagnosis and management of this life-threatening condition. [Level 5]
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