Risk assessment of adults with chemotherapy-induced neutropenia

INTRODUCTION — Cancer patients receiving systemic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria and/or fungi that translocate across intestinal mucosal surfaces damaged by cytotoxic therapy. Since the magnitude of the neutrophil-mediated component of the inflammatory response may be muted in neutropenic patients [1], a fever may be the earliest and only sign of infection.

It is critical to recognize neutropenic fever early and to initiate empiric systemic antibacterial therapy promptly to avoid progression to a sepsis syndrome and possibly death. It is also important to assess the risk for serious complications that may develop in patients with neutropenic fever, since this assessment will dictate the approach to therapy, including the need for inpatient admission, intravenous antibiotics, and prolonged hospitalization [2].

This topic will provide an overview of the risk assessment for patients with neutropenic fever. An overview of neutropenic fever syndromes and the prevention and treatment of neutropenic fever syndromes in cancer patients at high and low risk for serious complications are presented separately; the diagnostic approach to patients presenting with neutropenic fever is also discussed elsewhere. (See "Overview of neutropenic fever syndromes" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Diagnostic approach to the adult cancer patient with neutropenic fever".)

DEFINITIONS

Fever — Fever in neutropenic patients is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38°C (100.4°F) sustained over a one-hour period [2]. This is discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Definitions'.)

Neutropenia — The definition of neutropenia varies from institution to institution, but neutropenia is usually defined as an absolute neutrophil count (ANC) <1500 or 1000 cells/microL and severe neutropenia as an ANC <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL over the next 48 hours [2]. Profound neutropenia is defined as an ANC <100 cells/microL. The risk of clinically important infection rises as the neutrophil count falls below 500 cells/microL and is higher in those with a prolonged duration of severe neutropenia (>7 days). The risk for bacteremic infection rises as the ANC falls below 100 cells/microL. For the purposes of this discussion, we are defining severe neutropenia as an ANC <500 cells/microL.

The ANC can be calculated by multiplying the total white blood cell count by the percentage of polymorphonuclear cells and bands (calculator 1).

(See "Overview of neutropenic fever syndromes", section on 'Neutropenia' and "Overview of neutropenia in children and adolescents", section on 'Definitions and normal values' and "Approach to the adult with unexplained neutropenia", section on 'Definitions and normal values'.)

Assessment of the risk of neutropenia prior to having the results of the white blood cell count and differential is discussed separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Risk of neutropenia'.)

CATEGORIES OF RISK — There are at least three different categories of risk relevant to the assessment of neutropenic patients:

●The risk of developing a neutropenic fever syndrome (see 'Risk factors for neutropenic fever' below)

●The risk of developing medical complications as a result of the neutropenic fever syndrome that require hospitalization or prolong the length of stay (see 'Risk of serious complications' below)

●The risk of nonresponse to the empiric antibacterial treatment for the neutropenic fever syndrome (see 'Risk of treatment failure' below)

RISK FACTORS FOR NEUTROPENIC FEVER — The risk factors that are predictive of the development of a neutropenic fever syndrome can be divided into three subcategories: patient-related, disease-related, and treatment-related predictors [3].

Patient-related predictors — Patient-related predictors of the development of neutropenic fever include:

●Age (particularly 65 years or more) [4-7]

●Female sex [8]

●High body surface area [9]

●Poor performance status based upon pre-existing active cardiovascular, renal, endocrine, or pulmonary comorbidities [8,10]

●Poor nutritional status [11]

Disease-related predictors — Disease-related predictors of the development of neutropenic fever include:

●Elevated lactate dehydrogenase (LDH) in patients with lymphoreticular diseases [11]

●Myelophthisis (bone marrow failure due to replacement of hematopoietic tissue by abnormal tissue) [11]

●Lymphopenia [12,13]

●Advanced stage of the underlying malignancy [5,8,14-16]

Anti-cancer treatment-related predictors — Anti–cancer treatment–related predictors of the development of neutropenic fever include:

●Administration of the planned dose intensity or dose density of high-dose chemotherapy regimens [7,12,17-19]

●Failure to administer prophylactic hematopoietic growth factor support to patients receiving high-risk regimens [6,17] (see "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation")

●A number of variables have been associated with a higher risk for neutropenic fevers occurring during the first cycle of cancer chemotherapy with etoposide-based cytotoxic regimens including Karnofsky performance status (odds ratio [OR] 0.85, 95% CI 0.81-0.89), having three or more metastatic sites (OR 6.33, 95% CI 2.66-15.11), cardiovascular comorbidity (OR 4.88, 95% CI 1.74-13.67), recent surgery (OR 7.96, 95% CI 1.96-32.36), administration of alkylating agents (OR 4.50, 95% CI 1.10-18.48), total bilirubin ≥25 umol/L (OR 11.42, 95% CI 4.00-32.61), and absolute lymphocyte count of less than 0.7 x 10⁹/L (OR 4.22, 95% CI 2.00-9.75) [20].

RISK OF SERIOUS COMPLICATIONS — This risk assessment dictates the approach to therapy, including the need for inpatient admission, intravenous (IV) antibiotics, and prolonged hospitalization (table 1). High-risk patients require admission to hospital for IV antibiotics and often require a prolonged length of stay. By contrast, low-risk patients may be treated with oral antibiotics as outpatients after a brief period of observation or a short hospital admission. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

Validated scoring systems used to estimate the risk for medical complications include the Talcott rules [21], the Multinational Association for Supportive Care in Cancer (MASCC) score [14], and the Clinical Index of Stable Febrile Neutropenia (CISNE) score [22].

The risk assessment should also take into account infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most frequent presenting symptoms of coronavirus disease 2019 (COVID-19) include fever, cough, and difficulty in breathing, which overlap with common presentations of a spectrum of infectious and noninfectious respiratory syndromes among cancer patients. Although cancer patients are thought not to be greater risk for contracting COVID-19, the risk for more severe COVID-19-related sequelae appears to be greater. Further, the risk of SARS-CoV-2 transmission from patient to heath care provider must also be considered and guide the use of personal protective equipment and isolation procedures [23]. (See "COVID-19: Considerations in patients with cancer".)

Our definitions of low-risk and high-risk patients — We define low-risk and high-risk patients as follows; it should be noted that the Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) use different definitions in their guidelines (see 'IDSA risk assessment' below and 'NCCN risk assessment' below):

●Low-risk patients are defined as those who are expected to be severely neutropenic (absolute neutrophil count [ANC] <500 cells/microL) for ≤7 days and who have no active comorbidities or evidence of significant hepatic or renal dysfunction. This group of patients has been well studied in randomized trials and has been shown to be at low risk for serious complications [2]. Most patients receiving chemotherapy for solid tumors are considered to be low risk for complications requiring hospitalization or prolonging hospitalization.

●We define high-risk patients as those who are expected to be neutropenic (ANC <500 cells/microL) for >7 days. Patients with neutropenic fever who have ongoing comorbidities or evidence of significant hepatic or renal dysfunction are also considered to be high risk, regardless of the duration of neutropenia. Other criteria that confer a high-risk status can be found in the table (table 1).

Some experts have defined high-risk patients as those expected to have profound neutropenia (ANC ≤100 cells/microL) for >7 days based on experience that such patients are the most likely to have life-threatening complications [2,24,25]. However, formal studies to clearly differentiate between patients with an ANC <500 cells/microL and ≤100 cells/microL are lacking. For the purposes of this discourse, we will combine these groups. Profound prolonged neutropenia (ie, ANC ≤100 cells/microL expected to last >7 days) is most likely to occur in the pre-engraftment phase of myeloablative hematopoietic cell transplantation (HCT; particularly allogeneic) and in patients undergoing induction chemotherapy for acute leukemia.

Risk based on underlying disease — Patients who are neutropenic as a result of induction chemotherapy for acute myelogenous leukemia or as part of the conditioning regimen for allogeneic HCT are at particularly high risk for serious infections (table 2). Other factors that confer a high-risk status include oral and gastrointestinal mucositis, uncontrolled cancer, chronic obstructive pulmonary disease, poor functional status, and advanced age.

Patients undergoing autologous HCT or receiving consolidation chemotherapy for leukemia may also have prolonged periods of neutropenia but appear to be at somewhat lower risk, particularly if they are receiving prophylactic hematopoietic growth factors.

Patients with solid tumors are generally at low risk for serious infections.

Guidelines — The IDSA, the European Society of Medical Oncology, the NCCN, and the American Society for Clinical Oncology (ASCO) recommend that an assessment of risk (high risk versus low risk) for neutropenic fever–related medical complications should be obtained at the time of the initial assessment of the neutropenic fever episode [2,24,26,27].

The IDSA and ASCO defined high-risk neutropenic patients as those with an ANC ≤100 cells/microL expected to last >7 days or evidence of ongoing comorbid conditions or significant hepatic or renal dysfunction [2,27]. The NCCN has developed similar criteria but also includes an intermediate risk category [24]. In contrast with the IDSA, ASCO, and NCCN definitions, our definition of high-risk patients includes those who are expected to be neutropenic (ANC <500 cells/microL) for >7 days. (See 'Our definitions of low-risk and high-risk patients' above.)

The MASCC risk index is a validated tool for measuring the risk for neutropenic fever–related medical complications (calculator 2) [14,28-30]. The MASCC risk index may be used as an alternative to using clinical criteria to help in the selection of patients for whom outpatient oral initial empiric antibacterial therapy may be considered.

IDSA risk assessment — The Infectious Diseases Society of America has developed criteria for defining neutropenic patients as high risk or low risk when they present with a fever [2].

High risk — High-risk febrile neutropenic patients are defined as those with any of the following characteristics:

●ANC ≤100 cells/microL expected to last >7 days or

●Evidence of ongoing comorbid conditions, such as (but not limited to):

•Hemodynamic instability

•Oral or gastrointestinal tract mucositis limiting swallowing or causing severe diarrhea

•Gastrointestinal symptoms, such as abdominal pain, nausea and vomiting, or diarrhea

•Neurologic or mental status changes of new onset

•Intravascular catheter infection

•New pulmonary infiltrate or hypoxia

•Underlying chronic lung disease or

●Evidence of hepatic insufficiency (defined as aminotransferase levels >5 times normal values) or renal insufficiency (defined as a creatinine clearance <30 mL/min) [2]

The ASCO/IDSA guidelines suggest that despite a low-risk MASCC score of ≥21, the presence of characteristics such as these should discourage outpatient care strategies [27].

Profound prolonged neutropenia (ANC ≤100 cells/microL expected to last >7 days) is most likely to occur in the pre-engraftment phase of HCT (particularly allogeneic recipients receiving a myeloablative conditioning regimen) and in patients undergoing induction chemotherapy for acute leukemia.

Low risk — Low-risk febrile neutropenic patients are expected to have a duration of neutropenia (ANC <500 cells/microL) of 7 days or fewer and have no comorbidities or evidence of significant hepatic or renal dysfunction [2]. Most patients receiving chemotherapy for solid tumors are considered to be low risk for complications requiring hospitalization or prolonging hospitalization. Such patients would be represented among those satisfying the Talcott rule group IV or having a MASCC score ≥21 or CISNE score <3.

Patients presenting with evidence of severe sepsis (sepsis syndrome with end-organ dysfunction) should be regarded as high risk and managed with intravenously administered initial empiric antibacterial therapy and hospitalization. Patients with evidence of septic shock should be managed in a critical care hospital environment based upon goal-directed therapy [31]. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Evaluation and management of suspected sepsis and septic shock in adults".)

NCCN risk assessment — The National Comprehensive Cancer Network has developed criteria to categorize patients as high risk or low risk, which should be performed during the initial assessment [24].

High risk — The NCCN categorizes febrile neutropenic patients as high risk if any of the following criteria are met [24]:

●Inpatient status at time of development of fever

●Significant medical comorbidity or presence of clinical instability

●Anticipated prolonged profound neutropenia (ANC ≤100 cells/microL expected to last >7 days)

●Hepatic insufficiency (defined as aminotransferase levels >5 times normal values) or renal insufficiency (defined as a creatinine clearance <30 mL/min)

●Uncontrolled progressive cancer defined as any leukemic patient not in complete remission or any nonleukemic patient with evidence of disease progression after more than two courses of chemotherapy

●Pneumonia or other complex infection at clinical presentation

●Alemtuzumab within the past two months

●Grade 3 or 4 mucositis

●MASCC risk index score <21 (calculator 2)

Low risk — The NCCN categorizes febrile neutropenic patients as low risk for complications if they do not meet any of the high-risk criteria described above and if they meet most of the following criteria [24]:

●Outpatient status at time of development of fever

●No associated acute comorbid illness requiring inpatient hospitalization or close observation

●Anticipated short duration of severe neutropenia (ANC ≤100 cells/microL expected to last 7 days or fewer)

●Good performance status (Eastern Cooperative Oncology Group [ECOG] 0 to 1 (table 3))

●No hepatic insufficiency

●No renal insufficiency

●MASCC risk index score ≥21 (calculator 2) (see 'MASCC score' below)

Intermediate risk — In addition to the categories of high risk and low risk described above, the NCCN defines febrile neutropenic patients to be intermediate risk for complications if any of the following criteria are met [24]:

●Autologous HCT

●Lymphoma

●Chronic lymphocytic leukemia

●Multiple myeloma

●Purine analog therapy (see "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Purine analogs')

●Anticipated duration of neutropenia of 7 to 10 days

The NCCN recommends consideration of fluoroquinolone prophylaxis for intermediate-risk patients. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)

MASCC score — The Multinational Association for Supportive Care in Cancer risk index is a validated tool for measuring the risk for neutropenic fever–related medical complications [14,28-30,32]. The MASCC risk index may be used as an alternative to the clinical risk assessments described above. (See 'Our definitions of low-risk and high-risk patients' above and 'Guidelines' above.)

Using the MASCC risk index, the following characteristics are assessed and given a weighted score (calculator 2) [2,14]:

●Burden of illness (the general clinical status of the patient at the time of presentation with neutropenic fever)

•No or mild symptoms – 5

•Moderate symptoms – 3

•Severe symptoms or moribund – 0

●No hypotension (systolic blood pressure >90 mmHg) – 5

●No chronic obstructive pulmonary disease – 4

●Solid tumor or hematologic malignancy with no history of previous fungal infections – 4

●No dehydration requiring parenteral fluids – 3

●Outpatient status at the time of onset of the neutropenic fever syndrome – 3

●Age <60 years – 2

The maximum attainable score is 26. A score ≥21 predicts those patients at low risk for serious medical complications and those for whom outpatient management with an oral empiric antibacterial regimen may be safe and effective [30]. A score <21 predicts those patients at high risk for serious medical complications (see 'Serious medical complications' below). The MASCC risk index has correctly classified low-risk and high-risk patients in 98 and 86 percent of cases, respectively, giving a sensitivity, specificity, and positive and negative predictive value of 95, 95, 98, and 86 percent, respectively [29].

The reclassification of patients with "complicated" infections (defined by presence of a visceral site of infection, sepsis syndrome, nonnecrotizing skin or soft tissue infection [SSTI] of >5 cm diameter, necrotizing SSTI of any size, or oral mucositis [World Health Organization grade >2]) as high risk for serious medical complications has further increased the predictive value of the model [33]. The misclassification rate has been 10 to 29 percent [3].

In addition, the MASCC risk index may predict the likelihood of death as follows [28]:

●<15: 29 percent

●≥15 but <21: 9 percent

●≥21: 2 percent

A retrospective cohort study suggested that a mean C-reactive protein (CRP) concentration >150 mg/L (>15 mg/dL) together with a high-risk MASCC score is associated with a higher risk of 30-day all-cause mortality than a high-risk MASCC score and a mean CRP concentration <150 mg/L (<15 mg/dL; 36 versus 2 percent) [34]. In another study of 400 episodes of neutropenic fever in 355 patients, a baseline serum procalcitonin of ≥0.5 ng/mL, a MASCC score <21, and a platelet count of <100/microL were independent predictors of bacteremia [35]. Moreover, a baseline serum procalcitonin of ≥1.5 ng/mL and a MASCC score <21 were independent predictors of septic shock, suggesting that the availability of these results at presentation can be used to help clinicians make informed decisions regarding patient disposition. Serum procalcitonin (>0.25 ng/mL), serum lactate (>2.2 mmol/L), and MASCC score (<21) have been independent covariates of bloodstream infection in cancer patients presenting with febrile neutropenia [36].

One criticism of the MASCC risk index is the lack of a standardized definition of this criterion, "burden of febrile neutropenia," which might be confusing [2] or interpreted differently by different clinicians. Another important point is that the MASCC risk index does not include duration of neutropenia as a criterion, although this is considered an important predictor of risk [2].

Another criticism is that the MASCC risk index was developed using heterogeneous patient populations and that it may not perform optimally in all populations. As an example, in a retrospective study of outpatients with solid tumors who appeared to be clinically stable, the MASCC risk index had a low sensitivity to detect complications (36 percent) [37]. The low sensitivity was likely to be due to the fact that the patients were all outpatients and the rates of hypotension, dehydration, and invasive fungal infections were low; thus, only three criteria were present to make a prognostic distinction.

Serious medical complications — The serious medical complications predicted by the MASCC risk index include [14]:

●Hypotension (defined by a systolic blood pressure <90 mmHg or by the need for vasopressor support to maintain blood pressure)

●Respiratory failure (defined by an arterial oxygen pressure <60 mmHg while breathing room air or by the need for mechanical ventilation)

●Admission to a critical care service

●Disseminated intravascular coagulation

●Presence of confusion, delirium, or altered mental state

●Development of congestive cardiac failure documented by chest imaging and that requires treatment

●Bleeding diathesis sufficient to require blood cell transfusion

●Arrhythmia or electrocardiogram changes requiring treatment

●Renal failure sufficient to require investigation and/or treatment with IV fluids, dialysis, or any other intervention

●Other complications judged serious and clinically significant by the medical care team

Clinical Index of Stable Febrile Neutropenia — The Clinical Index of Stable Febrile Neutropenia (CISNE) is a validated scoring system that was developed to predict major complications in outpatients with solid tumors receiving mild- or moderate-intensity chemotherapy and who were experiencing a neutropenic fever syndrome but were clinically stable [22].

Points were assigned as follows in patients with any of the following variables associated with serious complications:

●Eastern Cooperative Oncology Group performance status ≥2 (table 3) – 2 points

●Chronic obstructive pulmonary disease – 1 point

●Chronic cardiovascular disease – 1 point

●Mucositis of grade ≥2 – 1 point

●Monocytes <200/microL – 1 point

●Stress-induced hyperglycemia – 2 points

Patients were then stratified into the following prognostic classes based upon their scores:

●Class I (low risk) – 0 points

●Class II (intermediate risk) – 1 to 2 points

●Class III (high risk) - ≥3 points

In the validation group, complication rates were 1.1 percent in class I patients, 6.2 percent in class II patients, and 36 percent in class III patients. Mortality rates were 0 percent in class I patients, 0 percent in class II patients, and 3.1 percent in class III patients. Using a cutoff of ≥3 points, for predicting major complications, the CISNE had sensitivity of 77.7 percent, specificity of 78.4 percent, positive predictive value of 36.1 percent, and negative predictive value of 95.7 percent. The predictive performance of the CISNE was better than that of the MASCC score, which is not surprising given the known limitations of the MASCC score in patients with solid tumors (see 'MASCC score' above). A subsequent study using a CISNE score cutoff of ≥1 points in febrile neutropenic patients presenting to two academic emergency departments similarly concluded that the CISNE score may be the best predictor for risk stratification in that setting [38]. A third study encompassing febrile neutropenic cancer patients from three tertiary cancer centers in South Korea, the United Kingdom, and the United States, 52 percent of whom had solid tumors, demonstrated a greater discriminating power for low-risk patients for the MASCC score (AUC 0.772; 95% CI 0.726-0.819) compared with the CISNE score (AUC 0.681; 95% CI 0.626-0.737) [39].

Experience tells us that outpatient management of febrile neutropenic patients at low-risk for complications is safe and effective but imperfect [40]. It seems clear that these predictive tools are useful; however, it remains unclear how they should be used: in isolation of one another or perhaps together in a sequence to provide a basis for informed clinical decisions.

Risk of sepsis — Although the signs and symptoms of infection may be significantly muted in neutropenic patients [1,41], an early part of the clinical assessment at triage should include an examination for evidence of a systemic inflammatory response syndrome (SIRS) and a determination of the criteria for sepsis, severe sepsis, and septic shock [42]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Definitions'.)

Patients presenting with evidence of new organ dysfunction (altered mental status, hypotension, hypoxia, or oliguria) should be managed emergently for severe sepsis. The following Algorithm provides a suggested time-dependent care pathway for neutropenic cancer patients presenting at an emergency triage facility based upon historical and observational clinical criteria assessable at presentation (algorithm 1). (See "Evaluation and management of suspected sepsis and septic shock in adults".)

RISK OF TREATMENT FAILURE — The risk of failure to respond to the initial empiric antibacterial therapy is a major risk that the clinician must consider. Treatment failure is a composite outcome that is defined by one or more of the following events occurring within 30 days of the start of treatment [40,43]:

●Death

●Persistence, progression, or recrudescence of signs and symptoms of infection

●Modification of the initial empiric antibacterial regimen

●For outpatients, readmission to the hospital

Several factors influence the risk of treatment failure:

●Treatment failure is more likely among patients with documented infections, clinical or microbiologic, than for unexplained neutropenic fevers (39 versus 18 percent) [44].

●Treatment failure occurs more often among high-risk patients than low-risk patients. As an example, patients with hematologic malignancies have a higher rate of treatment failure than those with solid tumors (44 versus 18 percent) [44].

●Among febrile neutropenic patients at low risk for medical complications, the treatment failure rate is higher for adults compared with children (16 versus 5 percent) [40].

●Delay in the institution of appropriate and effective antibacterial therapy [45,46]

●Poor baseline performance status (table 3) [47]

●Failure to administer guideline-driven initial empiric antibacterial therapy [48]

These observations underscore the prognostic importance of the underlying diagnosis, the risk category (high risk versus low risk), and the clinical characteristics of the neutropenic fever syndrome.

Outcomes are discussed in greater detail separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Outcomes' and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications", section on 'Outcomes'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Neutropenia and fever in people being treated for cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk categories − There are at least three different categories of risk relevant to the assessment of neutropenic patients:

•The risk of developing a neutropenic fever syndrome (see 'Risk factors for neutropenic fever' above)

•The risk of developing medical complications as a result of the neutropenic fever syndrome that require hospitalization or prolong the length of stay (see 'Risk of serious complications' above)

•The risk of nonresponse to the empiric antibacterial treatment for the neutropenic fever syndrome (see 'Risk of treatment failure' above)

●Risk factors − The risk factors that are predictive of the development of a neutropenic fever syndrome can be divided into three subcategories: patient-related, disease-related, and treatment-related predictors:

•Patient-related predictors include age (particularly 65 years or more), female sex, high body surface area, poor performance status (table 3), and poor nutritional status.

•Disease-related predictors include elevated lactate dehydrogenase in patients with lymphoreticular diseases, myelophthisis (bone marrow failure due to replacement of hematopoietic tissue by abnormal tissue), lymphopenia, and advanced stage of the underlying malignancy.

•Treatment-related predictors of neutropenic fever include administration of the planned dose intensity or dose density of high-dose chemotherapy regimens and failure to administer hematopoietic growth factor support to patients receiving high-risk regimens. (See 'Risk factors for neutropenic fever' above.)

●Risk assessment − We recommend that all patients presenting with neutropenic fever undergo a risk assessment for serious complications, since this assessment will dictate the approach to therapy (table 1). High-risk patients require admission to hospital for intravenous antibiotics and often require a prolonged length of stay. By contrast, low-risk patients may be treated with oral antibiotics as outpatients after a brief period of observation or a short hospital admission. (See 'Risk of serious complications' above and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

•High risk − We define high-risk patients as those who are expected to be severely neutropenic (absolute neutrophil count [ANC] <500 cells/microL) for >7 days. Patients with neutropenic fever who have ongoing comorbidities or evidence of significant hepatic or renal dysfunction are also considered to be high risk, regardless of the duration of neutropenia. Other criteria that confer a high-risk status can be found in the table (table 1). (See 'Our definitions of low-risk and high-risk patients' above.)

•Low risk − Low-risk febrile neutropenic patients are expected to have a duration of neutropenia (ANC <500 cells/microL) of 7 days or fewer and have no comorbidities or evidence of significant hepatic or renal dysfunction. These features are most commonly seen in patients with solid tumors. (See 'Low risk' above.)

●MASCC risk index − The Multinational Association for Supportive Care in Cancer (MASCC) risk index is a validated tool for measuring the risk for neutropenic fever–related medical complications (calculator 2). A score of ≥21 predicts those patients at low risk for serious medical complications and those for whom outpatient management with an oral empiric antibacterial regimen may be safe and effective. A score of <21 predicts those patients at high risk for serious medical complications. The MASCC risk index may be used in addition to the clinical criteria described above to help inform clinical decision-making. (See 'MASCC score' above.)

●Risk of treatment failure − Risk factors for treatment failure include the presence of a documented infection and high-risk status for serious complications (eg, hematologic malignancy). (See 'Risk of treatment failure' above.)