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Febrile neutropenia is a serious complication in patients receiving chemotherapy and is one of the most common causes of hospitalization in this population.1 This condition is considered an oncologic emergency, and if not addressed in a timely manner, it may progress to multiorgan system failure and may be fatal. Studies have shown that among patients who have neutropenic fever treated with empirical antibiotics, mortality rates range from 4% to 20%; among those who aren't treated with antibiotics, the mortality rate can be as high as 70%.2 The etiology of a fever in an oncology patient may be infectious or noninfectious; therefore, it's important to distinguish the cause to determine how to treat the patient properly. Noninfectious causes are mucositis, radiation, surgery, medications, and tumor fever, among others.3 Tumor fever is commonly associated with malignancies such as lymphoma, acute and chronic leukemia, and renal cell carcinoma, although almost all types of cancer may cause fever.3 The underlying mechanism that causes tumor fever is still unclear; however, it's thought that endogenous cytokines released by the tumor act as pyrogens (that is, they cause an inflammatory response and fever). Certain medications can also cause fever, such as immunosuppressants and antineoplastic (chemotherapeutic) agents.

Determining the origin of fever in patients receiving chemotherapy is further complicated by treatment-related suppression of bone marrow function (myelosuppression) that leads to a lower concentration of blood cells, which can cause a reduction in neutrophils.4 Neutrophils, created in the bone marrow, are the most abundant white blood cells in the human body and are considered the body's first responders to the acute inflammation that results from an invasion of pathogens. They're mobilized to the infection site and use various mechanisms, such as phagocytosis and release of chemicals, to break down and destroy the invaders. During chemotherapy, neutrophil proliferation is adversely affected as bone marrow is destroyed due to the chemotherapy drug's inability to differentiate between rapidly growing malignant cells and rapidly growing normal cells.5 Decreased neutrophils in the peripheral blood is known as neutropenia.4

The definition of neutropenia varies, but it's typically defined as an absolute neutrophil count (ANC) of less than 1,500 or 1,000 cells per microliter; severe neutropenia is defined as an ANC of less than 500 cells per microliter or an expected decrease below 500 cells per microliter within 48 hours.6 Patients who have both fever and neutropenia are considered to have febrile neutropenia.

A diagnosis of febrile neutropenia is given if a patient has a single oral temperature higher than 38.3°C (101°F) or higher than 38°C (100.4°F) sustained over an hour and an ANC of less than 500 cells per microliter or an ANC that's expected to fall below 500 cells per microliter within 48 hours.2, 7

In a patient with neutropenia, a fever may be the only indication of an infection because of the patient's inability to produce an inflammatory response.8 Nursing identification and management of neutropenic fever are instrumental in the rapid initiation of treatment and symptom management and can affect patient outcomes.9 The purpose of this article is to discuss the identification and management of febrile neutropenia in patients undergoing chemotherapy.

ETIOLOGY AND RISK FACTORS

Risk factors for neutropenia can be related to treatment (previous chemotherapy, irradiation of the bone marrow, and preexisting neutropenia) or cancer (bone marrow involvement of the tumor, hematologic malignancies, and advanced cancer).4 Specific risks can also be associated with different types of cancer. For example, in patients undergoing chemotherapy for solid tumors, neutropenia typically lasts less than seven days and only 5% to 30% of patients will go on to develop febrile neutropenia.2 In patients undergoing chemotherapy to treat blood cancers, the duration of neutropenia can last longer (about two weeks), with 80% of patients experiencing at least one episode of febrile neutropenia.

Chemotherapy-induced neutropenia rates are approximately 2.4 to 15.4 cases per million each year in the United States.6 Neutropenia can occur within the first week of chemotherapy as patients are reaching nadir, the point at which the white blood cell count is at its lowest, and neutropenia is often seen approximately five to 10 days after a chemotherapy cycle.2

A total of 20% to 30% of patients with febrile neutropenia develop complications that require hospitalization, and the overall in-hospital mortality rate is approximately 10%.10 The intensity of chemotherapy regimens for various cancers and the severity of neutropenia are classified as producing a low (less than 10%), intermediate (10% to 20%), or high (greater than 20%) risk of febrile neutropenia.10 Other factors or comorbidities that increase the risk of febrile neutropenia include older age, advanced disease, history of prior febrile neutropenia, mucositis, poor functional status with activities of daily living, and cardiovascular disease.

It's been estimated that up to 50% of patients with febrile neutropenia will develop an infection that can lead to sepsis, with sepsis being the leading cause of death in patients undergoing neutropenia-inducing treatment.9 Neutropenic patients at highest risk for developing sepsis are those with prolonged neutropenia (lasting longer than seven days), comorbidities, poor performance status (that is, a relatively poor ability to perform activities of daily living), and older age. Early identification of infection and proper treatment can potentially stop the trajectory of sepsis to septic shock, which causes cellular and metabolic abnormalities that lead to multiple organ failure and death.

Nurses may see patients with fever in a variety of clinical settings, such as EDs, urgent care centers, and outpatient clinics, as well as in the inpatient setting. No matter the setting, it's imperative that nurses are knowledgeable regarding the risk of sepsis in neutropenic patients and can identify early indicators of infection.9 With this knowledge, nurses can recognize signs of sepsis sooner and potentially reduce mortality in this patient population.

FEBRILE NEUTROPENIA: A CLINICAL SCENARIO

Ms. B. is a 70-year-old woman who presents to the ED with a reported fever (38.5°C [101.3°F]) and general malaise for the past three days. (This case is a composite based on our experience.) She was recently diagnosed with breast cancer and completed her first round of chemotherapy 10 days ago. She is unable to eat or drink because of mouth ulcers and reports feeling weak and dehydrated. She has a venous catheter implanted in her right chest wall that had been placed prior to the initiation of chemotherapy. The triage nurse recognizes that a fever after recent chemotherapy needs immediate attention because of the risk of infection and sepsis; the nurse is also aware that treating the patient within an hour of presentation is crucial for achieving a positive outcome. The triage nurse expedites Ms. B.'s evaluation and treatment. Ms. B.'s current vital signs are: temperature, 37.8°C; heart rate, 102 beats per minute; respiratory rate, 20 breaths per minute; blood pressure, 90/58 mmHg; and oxygen saturation by pulse oximetry (SpO2), 95% on room air.

The first hour. Ideally, the time from patient presentation in the ED to first administration of an antibiotic is less than one hour and includes drawing blood for laboratory tests. In patients presenting with fever, knowledge of their oncology history, cancer origin, chemotherapy regimen, and most recent chemotherapy cycle is an important part of the initial inquiry. In the case of Ms. B., the fact that her most recent chemotherapy cycle concluded 10 days earlier strongly suggests that she has reached nadir and has neutropenia. It's safe to assume that the fever means she has febrile neutropenia that requires immediate intervention and treatment. The American Society of Clinical Oncology, the Infectious Diseases Society of America, and the National Comprehensive Cancer Network (NCCN) recommend that a patient with confirmed or suspected febrile neutropenia be given empirical antibiotics within one hour of triage.7, 11 Strict adherence to this one-hour window is to prevent the cascade of the infectious process in patients whose clinical presentation may be subtle.12 NCCN guidelines recommend the following treatment and diagnostics11:

adequate IV access complete blood count (provides initial baseline neutrophil count to track progress) electrolytes, creatinine, and liver function tests (to determine the proper antimicrobial medication and dosage and provide a baseline from which to monitor for toxicities) serum lactate (to assess for tissue hypoxia and dysfunction that may result from the infectious process)13 blood cultures, two sets, taken peripherally or, if a central venous catheter is present, one peripheral and one from the catheter (to check for bacteremia and use to adjust the antibiotic dosage) IV monotherapy antibiotics

Delays in antibiotic administration are associated with a decrease in survival. For each hour of delay, there is a 7.6% increase in mortality.14 It's important for nurses to be aware of this important metric and to advocate for the timely administration of antibiotics.

Following the initial laboratory tests, a more detailed medical history and physical examination must be conducted to identify any current risk or source of infection and guide additional diagnostics.11 Sources of infection can include central venous catheters, lungs, sinuses, mouth, abdomen, perirectal area, and neurological system.2 In addition to physical assessment, a detailed history of medical comorbidities, a review of current systemic health, chemotherapy regimen and timing of cycle, prior infections, antibiotic prophylaxis, unwell social contacts, social and travel history, immunization status, and allergies (specifically penicillin) are important in determining the source of infection and should be identified in patients undergoing chemotherapy.2 In Ms. B.'s case, two possible sources of infection are her implanted venous access device and bacteria from her mouth ulcers migrating to her bloodstream.

For an algorithm on the assessment and management of cancer patients with neutropenic fever and suspected sepsis, go to https://links.lww.com/AJN/A246.

OUTPATIENT OR INPATIENT TREATMENT: RISK ASSESSMENT

Risk assessment tools can aid the health care team's decision-making regarding whether patients can be managed in the inpatient or outpatient setting by stratifying those who present with febrile neutropenia into low- or high-risk groups.15 The Multinational Association of Supportive Care in Cancer (MASCC) risk index is the most widely used risk assessment tool.7 The MASCC score is derived from weighted scores for seven variables that determine whether a patient has a low or high risk of a poor outcome, including death (see Table 1).7 The seven variables include symptom burden of febrile neutropenia, presence of hypotension, history of chronic obstructive lung disease, solid tumor or hematologic malignancy with previous fungal history, dehydration, outpatient status, and older age.2, 7 Patients with scores greater than or equal to 21 are considered to have a lower risk and a higher likelihood of a noncomplicated clinical course.15 Low scores are associated with poor outcomes and death.16 Incorporation of the MASCC score into decision-making not only identifies those patients at high risk for complications, it may also guide providers in the decision to admit a patient to a higher level of care or allow for earlier goals-of-care conversations if outcomes are expected to be poor.16

Table 1. - Determining the MASCC Score Characteristic Weight Burden of illness: no or mild symptoms 5 No hypotension (systolic blood pressure < 90 mmHg) 5 No chronic obstructive pulmonary disease 4 Solid tumor or no previous fungal infection 4 No dehydration 3 Burden of illness: moderate symptoms 3 Outpatient status 3 Age < 60 years 2

MASCC = Multinational Association of Supportive Care in Cancer.

Note: A MASCC score of ≥ 21 predicts a low risk of medical complications. Points attributed to the variable “burden of illness” are not cumulative. The maximum theoretical score is therefore 26. Adapted with permission from Klastersky J, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18(16):3038-51.

The NCCN 2022 guidelines add to the criteria that determine whether a patient is at low or high risk. In addition to a MASCC score greater than or equal to 21, criteria that place patients at low risk include being an outpatient at the onset of fever, having no acute comorbidities and no liver or kidney insufficiency, and having good performance status and a short anticipated duration of neutropenia.11 Patients must have all of these characteristics to be considered low risk.11 High-risk patients include those who have any one of the following characteristics: are inpatients at the onset of fever; have prolonged neutropenia, have comorbidities, or are clinically unstable; have hepatic or renal insufficiencies (or both), uncontrolled cancer, severe mucositis, or a stem cell transplant from a donor; use immune or targeted treatments (or both); or have a MASCC score of less than 21.11 Other factors include the expected duration of neutropenia; lower-risk patients have an expected duration of less than seven days and higher-risk patients, greater than seven days.11

Treatment of low-risk patients. Low-risk patients may be treated in the outpatient setting, either at home or in an ambulatory care clinic, provided that adequate infrastructure and a sufficient number of clinicians who can accurately assess risk are available.7 Not all ambulatory care clinics are equipped to treat neutropenia; therefore, the patient may require admission to the hospital for treatment. Hospital admissions can increase the risk of infection in this vulnerable population as well as increase health care costs, while outpatient treatment, on the other hand, can improve quality of life and patient satisfaction.17

Patients who meet the criteria for outpatient treatment will receive a first dose of empirical IV antibiotics in the clinic or ED and may be monitored for two to 12 hours before discharge to home, pending fever response and clinical stability.11 Specific logistical and psychosocial conditions must be met for outpatient treatment. Patients must live or be staying within one hour of a medical center and have adequate transportation, a telephone for follow-up, a thermometer, and a 24-hour caregiver; patients must also be amenable to home care services.11 Subsequent antibiotic therapy will most likely be administered orally; therefore, patients must be able to tolerate oral medications and have no nausea or vomiting and no indication or history of noncompliance.7 Following the NCCN 2022 guidelines, patients should have daily clinic or home care visits for 72 hours (about three days) followed by a daily phone call.11 Patients who have ongoing fever after two to three days of therapy, new signs and symptoms of infection, oral intolerance to medications, or a need to change antibiotics based on blood culture results should return to the clinic.11 Patients with febrile neutropenia in an outpatient setting are often treated with fluoroquinolones (ciprofloxacin or levofloxacin) and amoxicillin–clavulanate (or clindamycin in the case of a penicillin allergy).7 If outpatient therapy fails to yield better results, patients may need to be hospitalized.

Treatment of high-risk patients. Patients should be treated with a first dose of antibiotics within one hour of fever presentation, ideally after blood cultures are drawn.2 Patients in the inpatient setting typically receive a broad-spectrum β-lactam IV antibiotic with antipseudomonal activity, such as cefepime, cilastatin–imipenem, piperacillin–tazobactam, or ceftazidime.11

Patients with sepsis or a history of colonization with multidrug-resistant bacteria may begin with multiagent therapy that can be deescalated after laboratory results have been obtained and bacterial sensitivity to the antibiotic treatment has been determined.2

Hospitalized patients should be closely monitored for vital signs, and laboratory tests should be conducted every eight hours (or according to institutional policies, which may vary) to determine the direction therapy should take.18 The goal of therapy is to achieve clinical stability, decreasing fevers, and in some institutions, improvement in ANC to greater than or equal to 500 cells per microliter.2, 11 If the patient isn't responding or is worsening clinically, is persistently febrile, or has positive blood cultures, the antibiotic therapy may be changed.11 The patient may also have to have further diagnostics to determine the source of the infection.11 Special attention must be given to patients who present or develop abnormal vital signs, as this may indicate not just an infection but sepsis, which is associated with a higher incidence of hospital stays and mortality in the oncology population.19 Early warning scoring (EWS) tools or sepsis screenings have been implemented in various settings to improve sepsis treatment and management.20 Using clinical parameters such as temperature, heart rate, respiratory rate, systolic blood pressure, and central nervous system assessment, EWS tools (whether automated or handwritten) can help nurses with their assessments and identify patients with sepsis; in conjunction with early involvement of the ICU team, the mortality rate can be improved.20

Clinical scenario continued. Ms. B.'s level of risk is confirmed by using the MASCC risk index; her score is 16, less than 21, placing her at high risk for complications and a poor outcome. She has mild symptom burden with her mouth ulcers, is dehydrated with low blood pressure, and is over 70 years of age. She is admitted for treatment.

Despite the expedited triage, assessment, and first dose of empirical antibiotics, Ms. B.'s vital signs are retaken and are cause for alarm: temperature, 38.2°C; heart rate, 120 beats per minute; respiratory rate, 24 breaths per minute; and blood pressure, 83/50 mmHg. She is placed on supplemental oxygen to maintain an SpO2 over 95%. Her blood test results show a significantly low ANC of 400 cells per microliter and an elevated lactate level of 5.1 mmol/L.

FROM FEBRILE NEUTROPENIA TO SEPTIC SHOCK

In 2002, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine initiated the Surviving Sepsis Campaign (SSC), which issued clinical guidelines to improve the quality of sepsis care.19 According to the SSC guidelines, patients with neutropenia don't need to be treated differently from nonneutropenic patients.20 Recent updates to the guidelines emphasize five goals of care to be accomplished in the first hour of treatment: lactate level measurement; blood culture results; broad-spectrum antibiotic administration; rapid fluid resuscitation; and the addition of vasopressors to maintain a mean arterial pressure (MAP) greater than or equal to 65 mmHg (see The First Hour of Sepsis21).20 Elevated lactate levels (greater than 2 mmol/L) are an indication of increased oxygen consumption or decreased oxygen delivery to the tissues and organs (or both), indicating poor perfusion.19 If the patient is hypotensive or has a lactate level of 4 mmol/L or greater, 30 mL/kg of crystalloid fluid should be administered to improve blood pressure and clear the lactate.19, 21 Balanced crystalloid solutions that have an electrolyte composition closer to plasma, are preferred over normal saline, which can cause hyperchloremic metabolic acidosis and acute kidney injury.22 If blood pressure is unresponsive to fluid, then vasopressors should be initiated to perfuse organs and tissues.19 A MAP or an average arterial pressure throughout the cardiac cycle (systole and diastole) of at least 60 mmHg is required to perfuse vital organs, including the brain, kidneys, and liver.23 The first-line agent is norepinephrine, which increases blood pressure with minimal effect on heart rate.21 To avoid delay in initiation, norepinephrine may be administered peripherally until central-line access is obtained. When, despite adequate volume resuscitation, there is persistent hypotension requiring vasopressors to maintain a MAP greater than or equal to 65 mmHg and the serum lactate level is greater than 2 mmol/L, patients are in septic shock.20

Box 1: The First Hour of Sepsis21

Infection source control is a crucial part of the management of sepsis and septic shock and should be achieved as early as possible, preferably within six to 12 hours of initial resuscitation.21 It may include debridement of an infected wound, abscess drainage, or removal of vascular access devices.21 In the oncology population, intervention must not be delayed because of abnormalities in blood cell counts (red and white); blood products should be transfused as needed.20

Nursing interventions to support a patient with sepsis and septic shock should adhere to sepsis guidelines: ensure that blood cultures and lactate level are obtained and antibiotics are administered within one hour; administer oxygen and vasopressors to support vital signs; assess for adequate perfusion by measuring urine output; and assess temperature of extremities, skin mottling, and capillary refill time on an ongoing basis.21 Also, it's crucial that nurses communicate any abnormal findings to the provider for appropriate ongoing management.24 If ICU admission is required, it's important that it be timely to avoid longer hospital stays and greater risk of mortality.21

Clinical scenario conclusion. After she received 2.5 liters of a balanced crystalloid solution, Ms. B. required norepinephrine to maintain a MAP greater than or equal to 65 mmHg and was admitted to the ICU. Her implanted venous access device was removed as a possible source of infection. After two days, her lactate level and vital signs normalized, and she was transferred to a regular unit where a peripheral IV line was started to continue her antibiotics. She has been afebrile for 48 hours, is eating and drinking, and feels better overall. Early recognition and expedited care were crucial in Ms. B.'s positive outcome.

PREVENTION OF FEBRILE NEUTROPENIA

Prophylactic antibiotics. The use of antibiotic prophylaxis to prevent febrile neutropenia in patients undergoing mild to moderate intensity chemotherapy is not recommended because of the increased risk of infection with antibiotic-resistant bacterial pathogens.18, 25 Antibiotic prophylaxis should be limited to high-risk patients, such as those who are expected to have prolonged neutropenia (longer than seven to 10 days) as a result of the high-dose chemotherapy treatments associated with leukemia regimens and stem cell transplant.25

Neutrophil-stimulating medications. Granulocyte colony-stimulating factors (G-CSFs), such as filgrastim or pegfilgrastim, stimulate the production and function of granulocytes and neutrophils and can be administered to patients whose chemotherapy regimen places them at high risk for developing febrile neutropenia.26 In patients with solid tumors, for example, administration of G-CSFs after the first cycle of chemotherapy (known as primary prophylaxis) cuts the risk of febrile neutropenia by at least 50%.10 Patients may also receive G-CSF if undergoing a stem cell transplant and during acute leukemia therapy.

Patient education. Patient education is vital for infection prevention in vulnerable chemotherapy patients.24, 25 It's important for patients undergoing chemotherapy to be informed of the timing of neutropenia development,27 learn how to monitor for signs and symptoms of infections, and understand the urgency of seeing a health care provider if they develop a fever.24 Signs of infection may be subtle, and overlooking the most mundane symptom could have catastrophic results. Symptoms to note include chills or sweating; abdominal pain; diarrhea; cough; sore throat; anal pain; pain, burning, or frequency (or a combination of these) with urination; and redness, swelling, or pain (or a combination of these) at a wound or catheter site.27 It's important that oncology patients have consistent caregivers present during information sessions who are aware of the subtle changes that indicate infection in the absence of a fever and that require immediate attention.24

Additional infection prevention measures for the patient undergoing chemotherapy involve protecting the patient from infections in their own environment.25 Hand hygiene is important after using the bathroom and before handling food, as are good personal hygiene and oral care. Food must be properly handled, washed, and cooked. Patients should prevent skin injury by wearing gloves while cleaning, doing outdoor work, and when handling waste from pets.28, 29 They should also be aware that during nadir, when the ability to fight off infection is lowest, activities such as gardening, pet care, and attending events with large crowds should be avoided.28, 30 Patients must also limit exposure to communicable diseases by avoiding large crowds and be current with their vaccinations.28, 31

Annual influenza vaccination is recommended for oncology patients, their close contacts, and health care workers who work closely with patients.25 Patients must also receive the pneumococcal vaccine if not previously vaccinated. Timing of the injections, however, is dependent on whether patients have received specific therapies (chemotherapies or antibodies) in the previous six months. Live (attenuated) vaccines should not be administered while patients are undergoing chemotherapy or immunosuppressive therapy. It's important that patients collaborate with their oncologist to ensure that their vaccinations are up to date.

Implications for nursing practice. Any nurse who encounters a febrile patient with cancer who has had recent chemotherapy must recognize that prompt assessment and treatment is vital to recovery and survival. Nurses are in an excellent position to be able to identify any gaps in health care workers' adherence to guidelines, such as those from the SSC and the NCCN. Ongoing education for nurses and the health care team on the identification and appropriate triage of patients with fever and sepsis is crucial. When a fever is the only presenting symptom, undertriage can lead to delayed treatment and increased length of stay.12 Health care settings may have to redesign patient flow models to expedite care, incorporate clinical pathways and protocols, and standardize orders to ensure early intervention in the patient with febrile neutropenia. Nurses can participate in quality improvement initiatives that improve time to antibiotic administration and adherence to guidelines to ensure timely diagnostics and develop valid tools for clinical assessments and clinical pathways for management of febrile neutropenia.25

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