Febrile neutropenia

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List of terms related to Febrile neutropenia

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

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 the table. 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 bacteremia, either with a single organism or polymicrobial infection, but without a definable nonhematogenous site of infection, and 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.

”

Risk Assessment

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."

Clinical 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 criteria as follows:

• High-risk patients refer to those who

• have sustained, profound neutropenia anticipated to last >1 week or,
• are clinically unstable (eg, experience uncontrolled pain, altered mental status, or hypotension) or,
• have significant medical co-morbidities, such as uncontrolled cancer, chronic obstructive pulmonary disease, poor functional status, or advanced age.
• High-risk patients also may be identified by underlying cancer (eg, acute leukemia) and/or the intensity of chemotherapy undergone (eg, induction for acute leukemia or HSCT).

• Low-risk patients are clinically defined by neutropenia anticipated to last ≤7 days, are clinically stable, and have no medical comorbid conditions.

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

The Multinational Association for Supportive Care in Cancer (MASCC) Risk Index can be used to identify high-risk patients (score <21) and low-risk patients (score ≥21 points) for serious complications of febrile neutropenia (including death, intensive care unit admission, confusion, cardiac complications, respiratory failure, renal failure, hypotension, bleeding, and other serious medical complications). The score was developed to select patients for therapeutic strategies that could potentially be more convenient or cost-effective. The various variables and the weight of individual variables used in the MASCC risk index is as follows. To summarize, risk assessment helps determining the type of empirical antibiotic therapy, venue of the treatment, and duration of the antibiotic therapy.

Characteristic	Score
No or mild symptoms in patients following an episode of febrile neutropenia	5
Absence of hypotension with a systolic blood pressure >90 mmHg	5
No chronic obstructive pulmonary disease (active chronic bronchitis, emphysema, decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators)	4
Solid tumor or hematologic malignancy with no previously demonstrated fungal infection or empirically treated suspected fungal infection	4
Absence of dehydration that requires parenteral fluids	3
Moderate symptoms in patients following an episode of febrile neutropenia	3
Outpatient status	3
Age <60 years	2

A prospective trial demonstrated that a modified MASCC score can identify patients with febrile neutropenia at low risk of complications as well.

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.

See Also

• Neutropenia
• Leukopenia
• Fever
• Myelosuppression
• Chemotherapy

External Links

• Febrile neutropenia entry in the NCI Dictionary of Cancer Terms