Febrile neutropenia

Resident Survival Guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: F and N; fever and neutropenia; FN; neutropenic fever; neutropenic fever syndrome

Overview

Febrile neutropenia is a condition characterized by a decrease in neutrophils (neutropenia) associated with fever, the latter indicating the presence of an infection. The majority of patients have no identifiable site of infection and no positive culture results. Nonetheless, urgent therapy with empirical antibiotics is recommended in light of the possibility of rapid progression.

Historical Perspective

In 1966, Bodey et al. first described the quantitative association between leukocyte counts and the incidence of infection in a study of acute leukemia which demonstrated that the risk and the type of infection are related to the severity and duration of granulocytopenia. Infection risk begins to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm³ and rises markedly when the ANC drops to less than 500 cells/mm³. When the causative pathogen is identifiable, bacterial or viral etiology predominates within the first seven days of neutropenic fever, while infection with antibiotic-resistant bacteria or invasive fungi occurs more often in the setting of protracted neutropenia.

Pathophysiology

A number of factors pose an increased risk for infection in patients with neutropenic fever:

• Absolute or functional leukopenia

Leukocytes, particularly neutrophils, constitute one of the front-line defense mechanisms against invading microorganisms. Chemotherapy is associated with both qualitative and quantitative deficits in circulating neutrophils by lowering neutrophil counts and impairing chemotaxis and phagocytosis, respectively. In addition, patients receiving glucocorticoid-containing regimens, calcineurin inhibitors, or fludarabine are also predisposed to infection as a consequence of lymphocyte dysfunction.

• Altered microbiota

Microbiota that inhabit the skin, respiratory tract, and digestive tract may be altered by cancer and its treatment or the use of antibiotics.

• Breaches of natural barriers

Mucositis may occur as a direct adverse effect of chemotherapy or radiotherapy and disrupt the barrier function of the endothelial lining. Indwelling catheters and implanted devices allow access of skin commensals into blood or subcutaneous tissues or serve as a biofilm which bacteria can colonize.

• Immune defects associated with specific primary malignancies

An increased risk of infection has been observed in patients with Hodgkin's lymphoma (as a result of defects in cell-mediated immunity) and in patients with chronic lymphocytic leukemia or multiple myeloma (as a result of hypogammaglobulinemia).

Causes

Table 1. Common Bacterial Pathogens in Neutropenic Patients
Gram-Positive Pathogens
Coagulase-negative staphylococci Staphylococcus aureus, including methicillin-resistant strains Enterococcus species, including vancomycin-resistant strains Viridans group streptococci Streptococcus pneumoniae Streptococcus pyogenes
Gram-Negative Pathogens
Escherichia coli Klebsiella species Enterobacter species Pseudomonas aeruginosa Citrobacter species Acinetobacter species Stenotrophomonas maltophilia

Bloodstream infections caused by endogenous flora and reactivation of latent infections account for a majority of initial febrile episode in neutropenic patients with cancer. Common bacterial isolates that cause bacteremia in the setting of neutropenia are listed in Table 1. Certain endogenous microorganisms may be reactivated and exit latency during immunosuppression. These include herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, hepatitis B and C viruses, and Mycobacterium tuberculosis. Exogenous pathogens carried by contaminated blood products, medical equipment and devices, water sources, and health care workers represent less common sources of infection. These include Clostridium difficile, respiratory syncytial virus, vancomycin-resistant enterococci, and other multiresistant bacteria.

Fungal infections often take place in the setting of prolonged or profound neutropenia after administration of empirical therapy. Candidiasis may range in severity from mucosal or cutaneous infection to septicemia, endocarditis, or disseminated infection. Aspergillus, on the contrary, typically causes life-threatening infection of the sinuses and lungs, particularly after protracted neutropenia.

Epidemiology and Demographics

Approximately 10% to 50% of patients with solid tumors and more than 80% of those with hematologic malignancies will develop fever during courses of cytotoxic chemotherapy. However, an infectious etiology can be established in a minority of patients, and clinically defined infections occur in 20% to 30% of febrile episodes.

Over the past few decades, there has been a shift in the spectrum of bacterial isolates from patients with febrile neutropenia. Gram-negative organisms prevailed in the era when cytotoxic chemotherapy was initially introduced, whereas Gram-positive skin flora including coagulase-negative staphylococci evolved as the most common isolates after widespread use of indwelling catheters and prophylactic antibiotics. In addition, there has been a drift in susceptibility patterns, with resistance seen in the general population of hospitalized patients now emerging in febrile neutropenic patients.

Diagnosis

Diagnostic Criteria

The definitions of fever and neutropenia are used to identify patients in whom empirical antibiotic therapy must be initiated. However, neutropenic patients represent a heterogeneous population and treatment may be considered even when they do not meet these specific criteria. Clinical judgment based on parameters in risk assessment also plays a critical role in tailoring the management.

Fever

Fever is defined as a single oral temperature measurement of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a 1-hour period.

Neutropenia

Neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm³ or an ANC that is expected to decrease to <500 cells/mm³ during the next 48 hours.

Profound neutropenia

Neutropenia in which the ANC is <100 cells/mm³; a manual reading of the blood smear is required to confirm this degree of neutropenia.

Functional neutropenia

Functional neutropenia refers to patients whose hematologic malignancy results in qualitative defects (impaired phagocytosis and killing of pathogens) of circulating neutrophils. These patients should also be considered to be at increased risk for infection, despite a normal neutrophil count.

Microbiologically defined infection

This can include both

1. bacteremia, either with a single organism or polymicrobial infection, but without a definable nonhematogenous site of infection, and
2. a microbiologically defined site of infection (e.g., pneumonia, cellulitis) with or without concomitant bacteremia.

Clinically defined infection

This is designated when a site of infection is diagnosed (e.g., pneumonia,cellulitis) but its microbiologic pathogenesis either cannot be proven or is inaccessible to examination.

Unexplained fever

In the neutropenic patient, this is defined as a new fever that is not accompanied by either clinical or microbiologic evidence of infection.

History

Pertinent history should include new site-specific symptoms, prior use of antimicrobial agents, potential infection exposures, previous documented infections or pathogen colonization, catheter placement, and co-existence of noninfectious causes of fever, such as blood product administration. Underlying co-morbidities, such as diabetes, chronic obstructive lung disease, and/or recent procedures, should also be noted.

Signs and Symptoms

In neutropenic patients, manifestations secondary to inflammation are attenuated and fever is often the only clue indicative of an underlying infection.

Physical Examination

The physical examination should focus on potential sites of infection.

Skin

Induration and erythema may be minimal. Pustule formation are uncommon in the absence of neutrophils.

Throat

Examination of the oropharynx may reveal ulcers or plaques suggestive of herpes or candidiasis. Mucositis owing to cytotoxic chemotherapy may be indistinguishable from herpetic gingivostomatitis.

Lungs

Auscultation of the lungs may reveal minimal adventitial sounds.

Abdomen

Abdominal pain in neutropenic patients may herald an intraabdominal catastrophe secondary to neutropenic enterocolitis or tumor necrosis.

Other

Examination of catheter sites may disclose erythema, tenderness, or discharge.

Laboratory Findings

Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Initial Assessment

Class A

"1. Laboratory tests should include a CBC count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin. (Quality of Evidence: III)"

"2. At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing CVC, if present, and from a peripheral vein site; 2 blood culture sets from separate venipunctures should be sent if no central catheter is present. (Quality of Evidence: III)"

"3. Culture specimens from other sites of suspected infection should be obtained as clinically indicated. (Quality of Evidence: III)"

"4. A chest radiograph is indicated for patients with respiratory signs or symptoms. (Quality of Evidence: III)"

Class C

"1. Blood culture volumes should be limited to <1% of total blood volume (usually ~70 mL/kg) in patients weighing <40 kg. (Quality of Evidence: III)"

Risk Assessment

Table 2. Medical Complications Considered Serious
Hypotension: systolic blood pressure less than 90 mmHg or need for pressor support to maintain blood pressure Respiratory failure: arterial oxygen pressure less than 60 mmHg while breathing room air or need for mechanical ventilation Intensive care unit admission Disseminated intravascular coagulation Confusion or altered mental state Congestive cardiac failure seen on chest x-ray and requiring treatment Bleeding severe enough to require transfusion Arrhythmia or ECG changes requiring treatment Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention Other complications judged serious and clinically significant by the investigator†
† All reviewed by one investigator. Viral or fungal, microbiologically documented primary infection during the febrile episode, without any described complication and resolving under therapy, was considered a part of the infectious process and was not considered a serious complication.
Table 3. MASCC Risk Index Score
Characteristic Burden of febrile neutropenia with no or mild symptomsa No hypotension (systolic blood pressure >90 mmHg) No chronic obstructive pulmonary diseaseb Solid tumor or hematologic malignancy w/o prior fungal infectionc No dehydration requiring parenteral fluids Burden of febrile neutropenia with moderate symptomsa Outpatient status Age <60 years	Weight 5 5 4 4 3 3 3 2
The maximum value of the score is 26. a Burden of febrile neutropenia refers to the general clinical status of the patient as influenced by the febrile neutropenic episode. It should be evaluated on the following scale: no or mild symptoms (score of 5); moderate symptoms (score of 3); and severe symptoms or moribund (score of 0). Scores of 3 and 5 are not cumulative. b Chronic obstructive pulmonary disease means active chronic bronchitis, emphysema, decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators requiring treatment at the presentation of the febrile neutropenic episode. c Previous fungal infection means demonstrated fungal infection or empirically treated suspected fungal infection.

Infectious Diseases Society of America (IDSA) recommends that either the clinical judgment criteria or the MASCC assessment tool can be used to stratify risk for patients presenting with fever and neutropenia. Risk assessment should then inform decisions about the type of regimen and appropriate venue for delivery of empirical antibiotics, as well as the timing of hospital discharge. High-risk patients should initially receive IV empirical antibiotic therapy in the hospital, whereas low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.

Clinical Judgment Criteria

Patients with febrile neutropenia can be stratified at presentation into those with high-risk versus low-risk for complications of severe infection by the clinical judgment criteria as follows:

High-Risk Patient by Clinical Judgment Criteria

Patients with any of the following criteria are considered to be at high risk for serious complications during fever and neutropenia:

• Profound neutropenia (ANC ≤100 cells/mm³) anticipated to extend >7 days
• Presence of any co-morbid medical problems including but not limited to:

• Hemodynamic instability
• Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea
• Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea
• Neurologic or mental-status changes of new onset d Intravascular catheter infection, especially catheter tunnel infection
• New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease

• Evidence of hepatic insufficiency (defined as aminotransferase levels greater than 5 times of normal values) or renal insufficiency (defined as a creatinine clearance of less than 30 mL/min).

High-risk patients should be hospitalized and receive intravenous empirical antibiotic therapy.

Low-Risk Patient by Clinical Judgment Criteria

Patients with all of the following criteria are considered to be at low risk for serious complications during fever and neutropenia:

• Neutropenia expected to resolve within 7 days
• No active medical co-morbidity
• Stable and adequate hepatic function and renal function.

In general, any patient who does not strictly fulfill criteria for being at low risk should be treated according to guidelines for high-risk patients. Low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.

Multinational Association for Supportive Care in Cancer (MASCC) Risk Index

The MASCC scoring system is a summation of weighted factors, including patient age, history, outpatient or inpatient status, acute clinical signs, the presence of medical comorbid conditions, and severity of fever and neutropenia as assessed by burden of illness. The MASCC Risk Index can be used to identify subgroups of febrile neutropenic patients with high-risk (score <21) or low-risk (score ≥21) for serious complications and death (Table 2 and Table 3). It is also a means to determine which patients require prolonged hospitalization and which may be candidates for oral or once-daily IV regimens and/or for early discharge from the hospital to complete the antibiotic course as outpatients. A fundamental difficulty with the MASCC Risk Index is the indistinct nature of its major criteria: the "burden of febrile neutropenia" and associated symptoms. Without a clear standardized definition of this ‘‘burden’’ of disease, uniform application of the MASCC Risk Index may be confusing.

Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Risk Assessment

Class A

"1. Assessment of risk for complications of severe infection should be undertaken at presentation of fever. Risk assessment may determine the type of empirical antibiotic therapy (oral vs IV), venue of treatment (inpatient vs outpatient), and duration of antibiotic therapy. (Quality of Evidence: II)"

"2. Most experts consider high-risk patients to be those with anticipated prolonged (>7 days duration) and profound neutropenia (absolute neutrophil count [ANC] ≤100 cells/mm3 following cytotoxic chemotherapy) and/or significant medical co-morbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. Such patients should be initially admitted to the hospital for empirical therapy. (Quality of Evidence: II)"

"3. Low-risk patients, including those with anticipated brief (≤7 days duration) neutropenic periods or no or few co-morbidities, are candidates for oral empirical therapy. (Quality of Evidence: II)"

Class B

"1. Formal risk classification may be performed using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system. (Quality of Evidence: I) i. High-risk patients have a MASCC score <21. All patients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients. ii. Low-risk patients have a MASCC score ≥21. Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy."

Treatment

Generally, patients with febrile neutropenia are treated with empirical antibiotics until the neutrophil count has recovered (Absolute neutrophil counts greater than 500/mm3) and the fever has abated; if the neutrophil count does not improve, treatment may need to continue for two weeks or occasionally more. In cases of recurrent or persistent fever, an antifungal agent should be added.

Guidelines issued in 2002 by the Infectious Diseases Society of America recommend the use of particular combinations of antibiotics in specific settings; mild low-risk cases may be treated with a combination of oral co-amoxiclav and ciprofloxacin, while more severe cases require cephalosporins with activity against Pseudomonas aeruginosa (e.g. cefepime), or carbapenems (imipenem or meropenem). A subsequent meta-analysis published in 2006 found that cefepime was associated with more negative outcomes, and that carbapenems (while causing a higher rate of pseudomembranous colitis) were the most straightforward in use.

In 2010, an updated guidelines was issued by the Infectious Diseases Society of America, recommending use of cefepime, carbapenems (meropenem and imipenem/cilastatin), piperacillin/tazobactam for high risk patients and co-amoxiclav and ciprofloxacin for low risk patients. Patients who do not strictly fulfill the criteria of 'low risk patients' should be admitted to the hospital and treat as high risk patients.

Guideline Sources

• Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

See Also

• Neutropenia
• Leukopenia
• Fever
• Myelosuppression
• Chemotherapy

External Links

• Febrile neutropenia entry in the NCI Dictionary of Cancer Terms