Fever during chemotherapy-induced neutropenia may be the only indication of a severe underlying infection since signs and symptoms of inflammation typically are attenuated.
10% to 50% of patients with solid tumors and > 80% in those with hematologic malignancies will develop fever during one or more chemotherapy cycles associated with neutropenia.
All patients who present with fever and neutropenia should be treated empirically, swiftly and broadly, with antibiotics primarily directed against serious Gram-negative pathogens that may cause life-threatening sepsis.
Clinically documented infections occur in 20-30% of febrile episodes.
Common sites of tissue-based infection include the intestinal tract, lung, and skin.
Bacteremia occurs in 10-25% of all patients, with most episodes occurring in the setting of prolonged or profound neutropenia (absolute neutrophil count less than 100 neutrophils/mm3).
Resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE), have become more common and are the most prevalent resistant isolates in some centers, accounting for 20% to over 50% of episodes, respectively.
Penicillin-resistant strains of S. pneumoniae and of viridans group streptococci are less common but may cause severe infections.
Fungi are rarely identified as the cause of first fever early in the course of neutropenia. Rather, they are encountered after the first week of prolonged neutropenia and empirical antibiotic therapy.
Fever is defined as a single oral temperature measurement of ≥ 38.3°C (101°F) or a temperature ≥ 38.0°C (100.4°F) sustained over 1 hour.
Neutropenia is defined as an absolute neutrophil count (ANC) of less than 500 cells/mm3 or one that is expected to fall below 500/mm3 over the next 48 hours.
The term “profound” is sometimes used to describe neutropenia where the ANC is below 100 cells/mm3.
The term “functional neutropenia” refers to patients whose hematologic malignancy results in qualitative defects (impaired phagocytosis and killing of pathogens) of circulating neutrophils. These patients should be considered at increased risk for infection despite a “normal” neutrophil count.
Risk stratification is a recommended starting point for managing patients with fever and neutropenia.
Assessment of risk for complications of severe infection should be undertaken at presentation of fever (A-II).
Risk assessment may determine type of empirical antibiotic therapy (oral vs. intravenous [IV]), venue of treatment (inpatient vs. outpatient), and duration of antibiotic therapy (A-II).
High-risk patients — those with anticipated prolonged (> 7 days) and profound neutropenia (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 in hospital for empirical therapy (A-II).
Low-risk patients — those with anticipated brief (≤ 7 days) neutropenic periods and no or few co-morbidities — are candidates for oral empirical therapy (A-II).
Formal risk classification may be performed using the validated Multinational Association for Supportive Care in Cancer (MASCC) scoring system (B-I).
Diagnosis and Assessment
- Risk stratification is a recommended starting point for managing patients with fever and neutropenia.
- Assessment of risk for complications of severe infection should be undertaken at presentation of fever (A-II). Risk assessment may determine type of empirical antibiotic therapy (oral vs. intravenous [IV]), venue of treatment (inpatient vs. outpatient), and duration of antibiotic therapy (A-II).
- High-risk patients — those with anticipated prolonged (> 7 days) and profound neutropenia (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 in hospital for empirical therapy (A-II).
- Low-risk patients — those with anticipated brief (≤ 7 days) neutropenic periods and no or few co-morbidities — are candidates for oral empirical therapy (A-II).
- Formal risk classification may be performed using the validated Multinational Association for Supportive Care in Cancer (MASCC) scoring system (B-I).
Table 1. The MASCC Risk-Index Score
Characteristic and Weight
- Burden of febrile neutropenia with no or mild symptomsa
- No hypotension (systolic blood pressure > 90 mmHg)
- No chronic obstructive pulmonary disease
- Solid tumor or hematologic malignancy with no previous fungal infection
- No dehydration requiring parenteral fluids
- Burden of febrile neutropenia with moderate symptomsa
- Outpatient status
- Age < 60 years
NOTE: The maximum value of the score is 26. Scores below 21 are high risk (B-I).
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); severe symptoms or moribund (score of 0). Scores of 3 and 5 are not cumulative.
b Chronic obstructive pulmonary disease (active chronic bronchitis or emphysema) requiring a treatment at the presentation of the febrile neutropenic episode: decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators.
c Previous fungal infection: Demonstrated fungal infection or empirically treated suspected fungal infection.
Tests and Cultures
- Laboratory tests should include a complete blood count (CBC) with differential leukocytes and platelets, serum creatinine, blood urea nitrogen, electrolytes, hepatic transaminase enzymes, and total bilirubin (A-III).
- At least 2 sets of blood cultures are recommended:
- One set collected simultaneously from each lumen of an existing central venous catheter (if present) and from a peripheral vein site.
- 2 sets from separate venipunctures if no central catheter is present (A-III).
- Blood culture volumes should be limited to < 1% of total blood volume (usually approximately 70 mL/kg) in patients weighing < 40 kg (C-III).
- Culture specimens from other sites of suspected infection should be obtained as clinically indicated (A-III).
- A chest radiograph is indicated for patients with respiratory signs or symptoms (A-III).
Empiric Antibiotic Therapy
- High-risk patients require hospitalization for IV empirical antibiotic therapy: monotherapy with an anti-pseudomonal β-lactam agent such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam (A-I). Other antimicrobials (aminoglycosides, fluoroquinolones and/or vancomycin) may be added to the initial regimen for management of complications (ie, hypotension, pneumonia) or if antimicrobial resistance is suspected or proven (B-III).
- Vancomycin (or other agents active against aerobic Gram-positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia (A-I). (See Table 4 for indications.)
- Modifications to initial empirical therapy may be considered for patients at risk for infection with MRSA, VRE, extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria and carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC) bacteria, particularly if the patient is unstable or has positive blood cultures suspicious for resistant bacteria (B-III). Risk factors include previous infection or colonization with the organism or treatment in a hospital with high endemic rates.
- Most penicillin-allergic patients tolerate cephalosporins, but those with a history of an immediate-type hypersensitivity reaction (hives, bronchospasm) should be treated with a combination that avoids β-lactams and carbapenems, such as ciprofloxacin plus clindamycin, or aztreonam plus vancomycin (A-II).
- Afebrile neutropenic patients who have new signs or symptoms suggesting infection should be evaluated and treated as high-risk patients (B-III).
- Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting. They may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria (A-I).
- Ciprofloxacin plus amoxicillin/clavulanate in combination is recommended for oral empirical treatment (A-I). Other oral regimens, including levofloxacin or ciprofloxacin monotherapy, or ciprofloxacin plus clindamycin, are less well studied but are commonly used (B-III).
- Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone (A-III).
- Hospital re-admission or continued stay in the hospital is required for persistent fever, or signs and symptoms of worsening infection (A-III).
Modifying Antibiotic Therapy
- Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data (A-II).
- Unexplained persistent fever in an otherwise stable patient rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly (A-I).
- Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and susceptibilities of any isolated organisms (A-I).
- If vancomycin or other Gram-positive coverage was started initially, it may be stopped after 2 days if there is no evidence for a Gram-positive infection (A-II).
- Patients who are hemodynamically unstable should have their antimicrobial regimen broadened to include coverage for resistant Gram-negative, Gram-positive, and anaerobic bacteria and fungi (A-III).
- Low-risk patients who have been started on IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable (A-I).
- An IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate (A-I).
- Selected hospitalized patients who meet low-risk criteria may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured (B-III).
- If fever persists or recurs within 48 hours in outpatients, hospital re-admission is recommended, with management as for high-risk patients (A-III).
- Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4-7 days of a broad-spectrum antibacterial regimen and no identified fever source (A-II).
Duration of Antibiotic Therapy
- In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site. Appropriate antibiotics should continue for at least the duration of neutropenia (until ANC ≥ 500 cells/mm3) or longer if clinically necessary (B-III).
- In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery. The traditional endpoint is a rising ANC that exceeds 500 cells/mm3 (B-II).
- Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery (C-III).
- Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC ≤ 100 cells/mm3 for > 7 days) (B-I).
- Levofloxacin and ciprofloxacin have been evaluated most comprehensively and are considered roughly equivalent, although levofloxacin is preferred in situations with increased risk for oral mucositis-related invasive viridans group streptococcal infection.
- A systematic strategy for monitoring the development of fluoroquinolone resistance among Gram-negative bacilli is recommended (A-II).
- Addition of a Gram-positive active agent to fluoroquinolone prophylaxis is generally not recommended (A-I).
- Antibacterial prophylaxis is not routinely recommended for low-risk patients who are anticipated to remain neutropenic for < 7 days (A-III).
Empiric or Pre-Emptive Antifungal Therapy
- Empirical antifungal therapy and investigation for invasive fungal infections should be considered for patients with persistent or recurrent fever after 4-7 days of antibiotics and whose overall duration of neutropenia is expected to be > 7 days (A-I). Data are insufficient to recommend a specific empirical antifungal agent for a patient already on anti-mold prophylaxis, but switching to a different class of anti-mold antifungal given intravenously should be considered (B-III).
- Pre-emptive antifungal management is acceptable as an alternative to empirical antifungal therapy in a subset of high-risk neutropenic patients. Those who remain febrile after 4-7 days of broad-spectrum antibiotics but are clinically stable, have no clinical or chest and sinus CT scan signs of fungal infection, have negative serologic assays for evidence of invasive fungal infection, and no recovery of fungi such as Candida or Aspergillus from any body site, may have antifungal agents withheld (B-II). Antifungal therapy should be instituted if any of these indicators of possible invasive fungal infection are identified.
- In low-risk patients, the risk of invasive fungal infections is low so that routine use of empirical antifungal therapy is not recommended (A-III).
- Prophylaxis against Candida infections is recommended in patient groups in whom the risk of invasive candidal infections is substantial, such as allogeneic hematopoietic stem cell transplant (HSCT) recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia (A-I). Fluconazole, itraconazole, posaconazole, voriconazole, caspofungin or micafungin are all acceptable alternatives.
- Prophylaxis against invasive Aspergillus infections with posaconazole should be considered for selected patients 13 years and older who are undergoing intensive chemotherapy for acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) in whom the risk of invasive aspergillosis without prophylaxis is substantial (B-I).
- Prophylaxis against Aspergillus infection in pre-engraftment allogeneic or autologous transplant recipients has not been shown to be efficacious. However, a mold-active agent is recommended in patients with prior invasive aspergillosis (A-III), anticipated prolonged neutropenic periods of at least 2 weeks (C-III), or a prolonged period of neutropenia immediately prior to HSCT (C-III).
- Antifungal prophylaxis is not recommended for patients in whom the anticipated duration of neutropenia is < 7 days (A-III).
- Herpes simplex virus (HSV)-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I).
- Antiviral treatment for HSV or varicella-zoster virus (VZV) is indicated only if there is clinical or laboratory evidence of active viral disease (C-III).
- Respiratory virus testing (including influenza, parainfluenza, adenovirus, respiratory syncytial virus [RSV], and human metapneumovirus) and chest radiography are indicated for patients with upper respiratory symptoms (eg, coryza) and/or cough (B-III).
- Yearly influenza vaccination with inactivated vaccine is recommended for all patients being treated for cancer (A-II). Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (more than 7 days after the last treatment) or more than 2 weeks before chemotherapy starts (B-III).
- Influenza virus infection should be treated with neuraminidase inhibitors, if susceptible (A-II). In the setting of an influenza exposure or outbreak, neutropenic patients presenting with influenza-like illness should receive treatment empirically (C-III).
- Routine treatment of RSV in neutropenic patients with upper respiratory disease should not be given (B-III).
Hematopoietic Growth Factors (G-CSF or GM-CSF)
- Prophylactic use of myeloid colony-stimulating factors (CSFs; also referred to as hematopoietic growth factors) should be considered for patients in whom the anticipated risk of fever and neutropenia is 20% or greater (A-II).
- CSFs are not generally recommended for treatment of established fever and neutropenia (B-II).
Central Line-Associated Bloodstream Infections (CLABSI)
- Differential time to positivity (DTP) > 120 minutes of simultaneously drawn qualitative blood cultures from the central venous catheter and a vein suggests a CLABSI (A-II).
- For CLABSI caused by S. aureus, P. aeruginosa, fungi, or mycobacteria, catheter removal is recommended in addition to systemic antimicrobial therapy for at least 14 days (A-II).
- Catheter removal is also recommended for tunnel infection or port pocket site infection, septic thrombosis, endocarditis, sepsis with hemodynamic instability, or bloodstream infection that persists despite ≥ 72 hours on appropriate antibiotics (A-II).
- For documented CLABSI caused by coagulase-negative staphylococci, the catheter may be retained using systemic therapy with or without antibiotic lock therapy (B-III).
- Prolonged treatment (4-6 weeks) is recommended for complicated CLABSI, defined as the presence of deep tissue infection, endocarditis, septic thrombosis (A-II) or persistent bacteremia or fungemia occurring > 72 hours after catheter removal on appropriate antimicrobials (A-II for S. aureus, C-III for other pathogens).
- Practice hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine for all central venous catheter insertions (A-I).
- Hand hygiene is the most effective means of preventing transmission of infection in the hospital (A-II).
- Standard barrier precautions should be followed for all patients and infection-specific isolation for patients suspected of having transmissable infections (A-III).
- HSCT recipients should be placed in private (ie, single-patient) rooms (B-III). Allogeneic HSCT recipients should be placed in rooms with > 12 air exchanges/hour and high-efficiency particulate air (HEPA) filtration (A-III).
- Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III).
- Hospital work exclusion policies should be designed to encourage health care workers to report their illnesses or exposures (A-II).
Table 2. Common Bacterial Pathogens in Neutropenic Patients
Common Gram-positive Pathogens
- Coagulase-negative staphylococci Staphylococcus aureus, including methicillin-resistant isolates Enterococcus species, including vancomycin-resistant isolates Viridans group streptococci Streptococcus pneumoniae Streptococcus pyogenes
Common Gram-negative Pathogens
- Escherichia coli Klebsiella species Enterobacter species Pseudomonas aeruginosa Citrobacter species Acinetobacter species Stenotrophomonas maltophilia