Febrile neutropenia overview

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Overview
Historical Perspective
Pathophysiology
Causes
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
Initial Assessment
History and Symptoms
Physical Examination
Laboratory Findings
Chest X Ray
CT
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: F and N; fever and neutropenia; FN; hot and low; hot leuk; neutropenic fever; neutropenic fever syndrome; neutropenic sepsis

Overview

Febrile neutropenia is a condition characterized by a decrease in neutrophils (neutropenia) associated with the development of 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 treatment 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

Factors contributing to neutropenia fever entail absolute or functional leukopenia, altered microbiota, breaches of natural barriers, immune defects associated with specific primary malignancies, hyposplenism, and lymphotoxicity.

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.

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.

Risk Factors

Patients with an anticipated duration of neutropenia longer than 10 days, patients undergoing intensive induction/consolidation therapy for acute leukemias, patients receiving treatment with alemtuzumab-containing regimens, allogeneic HSCT recipients, and those with GVHD following allogeneic HSCT are categorized as high risk for infectious complications.

NCCN Overall Infection Risk Categories

The National Comprehensive Cancer Network (NCCN) devised a set of overall infection risk categories (low, intermediate, and high) in patients with cancer based on factors such as the underlying malignancy, disease status (eg, active disease, disease in remission), duration of neutropenia, prior exposure to chemotherapy, and intensity of immunosuppressive therapies.

Low risk for infectious complications

Patients with solid tumors undergoing standard chemotherapy regimens and who have an anticipated duration of neutropenia less than 7 days are considered at low risk for infectious complications.

Intermediate risk for infectious complications

Intermediate risk refer to patients with an anticipated duration of neutropenia of 7 to 10 days. Patients with lymphoma, multiple myeloma, or CLL; autologous HSCT recipients; or patients receiving treatment with purine analogue-containing regimens are also considered intermediate risk.

High risk for infectious complications

Patients with an anticipated duration of neutropenia longer than 10 days, patients undergoing intensive induction/consolidation therapy for acute leukemias, patients receiving treatment with alemtuzumab-containing regimens, allogeneic HSCT recipients, and those with GVHD following allogeneic HSCT are categorized as high risk for infectious complications.

Complications

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.

Potential complications of febrile neutropenia include hypotension, respiratory failure, disseminated intravascular coagulation, confusion or altered mental state, congestive heart failure, bleeding, arrhythmia, and renal failure.

Diagnosis

Diagnostic Criteria

According to the IDSA Practice Guideline, 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, and 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.

Initial Assessment

Either the clinical judgment criteria or the MASCC assessment tool can be used to stratify risk for patients presenting with fever and neutropenia. Initial 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.

History

Pertinent history should include new site-specific symptoms, prior use of antimicrobial agents, potential infection exposures, previous documented infections or pathogen colonization, catheter or device 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. Induration and erythema of the skin may be minimal. Pustule formation are uncommon in the absence of neutrophils. 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. Auscultation of the lungs may reveal minimal adventitial sounds. Abdominal pain in neutropenic patients may herald an intraabdominal catastrophe secondary to neutropenic enterocolitis or tumor necrosis. Examination of catheter sites may disclose erythema, tenderness, or discharge.

Laboratory Findings

Complete blood cell count with differential white cell count and levels of serum creatinine and urea nitrogen are required for determining the severity of neutropenia and monitoring potential drug toxicity. At least two sets of blood culture samples, each consisting of ~20 mL of blood divided into 1 aerobic and 1 anaerobic blood culture bottle, should be obtained from both a peripheral vein and from each catheter lumen.

Chest X Ray

Chest radiography should be reserved for patients with symptoms of respiratory tract infection.

CT

CT scan of the head, sinuses, abdomen, and pelvis may be performed if clinically indicated.

Other Diagnostic Studies

Routine test of inflammation markers, such as C-reactive protein, IL-6, IL-8, or procalcitonin, to guide clinical decisions is not recommended.

Medical Therapy

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 counts fail to restore, treatment may need to continue for two weeks or more. In cases of recurrent or persistent fever, an antifungal agent should be added.

Primary Prevention

Table 4. Antimicrobial Prophylaxis for Cancer-Related Infections
Low Risk
Bacterial - None Fungal - None Viral - None except positive HSV serology
Intermediate Risk
Bacterial - Consider fluoroquinolone prophylaxis Fungal - Consider antifungals during neutropenia and for anticipated mucositis Viral - During neutropenia and at least 30 days after HSCT
High Risk
Bacterial - Consider fluoroquinolone prophylaxis Fungal - Consider antifungals during neutropenia and for anticipated mucositis Viral - During neutropenia and at least 30 days after HSCT; also consider pre-emptive therapy against CMV or HBV
Table 5. Antifungal Prophylaxis in Patients with Cancer
Disease/Therapy ALL AML MDS Autologous HSCT with mucositis Allogenic HSCT GVHD	Antifungal prophylaxis Fluconazole Posaconazole Posaconazole Fluconazole or micafungin Fluconazole or micafungin Posaconazole

According to the NCCN Overall Infection Risk Categories, antimicrobial prophylaxis with fluoroquinolones may be considered in intermediate-risk or high-risk patients. Antifungal, antiviral, and anti-Pneumocystis jirovecii prophylaxis should be initiated in a targeted populations based upon the history, comorbidity, and serology.