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Diagnostic approach to the adult cancer patient with neutropenic fever

Diagnostic approach to the adult cancer patient with neutropenic fever
Author:
John R Wingard, MD
Section Editor:
Eric Bow, MD
Deputy Editor:
Sheila Bond, MD
Literature review current through: Aug 2022. | This topic last updated: Dec 08, 2020.

INTRODUCTION — Fever occurs frequently in patients with chemotherapy-induced neutropenia. Factors that contribute to the pathogenesis of neutropenic fever include the direct effects of chemotherapy on mucosal barriers and immune deficits related to the underlying malignancy or other immunosuppressive conditions or therapies. Prior to the era of empiric antibiotic therapy, infections accounted for most episodes of neutropenic fever and approximately 70 percent of the mortality in neutropenic acute leukemia patients [1]. Because of the routine use of prompt empiric antibiotics, infections are documented less frequently today.

Although the majority of patients with neutropenic fever do not have a documented infection, consensus guidelines recommend that all cancer patients with neutropenic fever be promptly evaluated and treated with empiric broad-spectrum antibiotics [2]. This approach is indicated since it is difficult to distinguish life-threatening infections from less serious infections in this patient population, and infection may progress rapidly in such patients. Furthermore, better outcomes are seen with prompt therapy [3].

The recommendations below are generally in keeping with the 2010 Infectious Diseases Society of America (IDSA) guidelines for the use of antimicrobial agents in neutropenic patients with cancer and the 2018 American Society of Clinical Oncology/IDSA guidelines for outpatient management of fever and neutropenia in adults treated for malignancy [2,4].

The diagnostic evaluation of cancer patients presenting with neutropenic fever will be reviewed here. An overview of neutropenic fever syndromes as well as the risk assessment and management of patients with neutropenic fever are presented separately. (See "Overview of neutropenic fever syndromes" and "Risk assessment of adults with chemotherapy-induced neutropenia" 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 "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".)

DEFINITIONS

Fever — Fever in neutropenic patients is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period [2]. The definition of fever is discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Fever'.)

Neutropenia — The definition of neutropenia may vary from institution to institution, but neutropenia is usually defined as an absolute neutrophil count (ANC) <1500 or 1000 cells/microL, severe neutropenia is as an ANC <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL over the next 48 hours, and profound neutropenia as an ANC <100 cells/microL [2,4,5]. 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 neutropenia (>7 days). 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 (WBC) count by the percentage of polymorphonuclear cells (PMNs) and bands (calculator 1). (See "Overview of neutropenic fever syndromes", section on 'Neutropenia'.)

Assessment of the risk of neutropenia before the WBC and differential results are available 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'.)

MICROBIOLOGY — Bacteremia is documented in only 10 to 25 percent of neutropenic fever episodes, and clinically documented infections are found in 20 to 30 percent [2]. Most documented infections during neutropenia are due to bacteria. Although gram-negative organisms predominated a few decades ago, most documented infections are now due to gram-positive organisms. Factors contributing to this trend include use of long-term central venous catheters and empiric and prophylactic antimicrobials that are primarily active against gram-negative pathogens. Fungi and viruses can also be pathogens, particularly in high-risk patients. (See "Overview of neutropenic fever syndromes", section on 'Epidemiology'.)

PATIENT EVALUATION — In all cancer patients presenting with neutropenic fever, empiric antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed. (See 'Initiation of empiric therapy' below.)

All patients should undergo a careful history and detailed physical examination as well as laboratory, microbiology, and imaging studies; the approach to the diagnostic evaluation is summarized in the following table (table 1). Because symptoms and signs of infection are attenuated due to the lack of an inflammatory reaction, fever may be the sole sign of infection. Thus, it is important to recognize that the absence of the typical symptoms, signs, or laboratory findings suggestive of infection typically seen in non-neutropenic patients cannot be used to exclude the possibility of infection. The evaluation should be performed promptly.

History — The history should probe for the development of new symptoms that can lead to identification of a site of infection. The initial clinical evaluation also focuses on assessing the risk of serious complications. (See 'Risk assessment' below.)

The following key elements of the history should always be included:

Inquire about organ-specific symptoms. A review of systems should be repeated daily. Determine if antimicrobial prophylaxis had been given and which agent(s).

Probe for a history of prior infection or colonization (especially by antibiotic-resistant organisms).

Determine if there might be noninfectious causes of fever (eg, blood transfusion, uncontrolled cancer).

Determine which comorbid conditions may be present. A variety of comorbid conditions predispose to infectious complications, such as immobility (decubitus ulcers), poor nutrition, foreign bodies such as venous or bladder catheters, prosthetic heart valves or orthopedic hardware, diabetes mellitus, chronic respiratory conditions, rheumatologic disorders, inflammatory bowel disease, etc.

Risk assessment — The initial clinical evaluation focuses on assessing the risk of serious complications in addition to the presence of a documented infection. The risk assessment dictates the approach to therapy, including the need for inpatient admission, intravenous (IV) antibiotics, and prolonged hospitalization. The factors that are associated with serious complications are summarized in the table (table 2) and discussed in greater detail separately. (See "Overview of neutropenic fever syndromes", section on 'Risk of serious complications' and "Risk assessment of adults with chemotherapy-induced neutropenia".)

Physical examination — A thorough general physical examination should be performed. The emphasis should be on sites most likely to be infected, including the skin, catheter sites, biopsy and bone marrow aspirate sites, teeth, oropharynx and gingival surfaces, sinuses, lungs, abdomen, genitals, and perianal area. As noted above, it is important to remember that in the absence of neutrophils, signs of inflammation can be extremely subtle.

Review of systems and a physical examination should be repeated daily. In patients with persistent fever, new sites of infection (eg, lungs, skin, and urinary tract) may become apparent over time. In addition, as the neutrophil count recovers, localizing symptoms and signs of infection often become evident for the first time.

Lungs — The lungs are a common site of infection in patients with chemotherapy-induced neutropenia and should be examined for signs of pneumonia (eg, rales). Hypoxia, tachypnea, and increased work of breathing are other signs of pneumonia. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Abdomen — An abdominal examination should be performed to evaluate for peritoneal signs and/or abdominal tenderness, which may represent neutropenic enterocolitis or Clostridioides difficile colitis. Even when an abdominal process is present, abdominal signs may be subtle or absent in neutropenic patients. (See "Neutropenic enterocolitis (typhlitis)" and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)

Intravenous catheter sites — All IV catheter sites, especially central venous catheter (CVC) sites, should be carefully examined for subtle signs of infection; slight erythema or tenderness may be the only evidence of a serious "tunnel" infection. Fluctuance or exudates are unlikely since the lack of inflammatory cells inhibits the development of inflammatory reactions. IV catheters should also be assessed for any malfunction; difficulty with infusion or blood drawing can also be a sign of an infected venous thrombosis, even in the absence of a problem with the exit site. Sites of recent IV catheters should also be examined.

Skin and mucous membranes — The skin and mucous membranes should be examined for signs of erythema, rash, cellulitis, ulcers, furuncles, vesicles, paronychia, mucositis, dental or peritonsillar cellulitis, perianal fissures, and pilonidal disease. Skin lesions can often be a manifestation of a systemic infection including:

Ulcers – Fungi, atypical bacteria, nontuberculous mycobacteria, viruses

Vesicles – Viruses

Nodules – Fungi, bacteria, nontuberculous mycobacteria

Ecthyma gangrenosum – Large lesion with a necrotic center that is classically seen with Pseudomonas aeruginosa but also with other bacteria, such as Staphylococcus aureus (picture 1)

Skin lesions with a necrotic center – Invasive fungal infections (eg, Fusarium spp, Aspergillus spp, Mucorales) can also cause skin lesions with a necrotic center (picture 2 and picture 3)

Sometimes, skin lesions, such as erythema multiforme, can be related to viral infections; alternatively, erythema multiforme can be related to antibiotic therapy and may be associated with fever, causing diagnostic confusion (picture 4). (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Infections that can cause fever and rash in immunocompromised hosts are discussed in greater detail separately. (See "Fever and rash in immunocompromised patients without HIV infection".)

Perianal region — The examination should also include inspection of the perianal area. Erythema, pain on palpation, and tender hemorrhoids are important signs of infection. However, digital rectal examination (and rectal temperatures) should be avoided so that one does not introduce infection by traumatizing the fragile mucosa.

Routine laboratory tests — Laboratory evaluation should include a complete blood cell count with differential, hepatic transaminases, bilirubin, electrolytes, serum creatinine, blood urea nitrogen, serum lactate, urinalysis, and cultures (table 1) [2].

In interpreting laboratory results in neutropenic patients, it is important to recognize that the absence of the typical laboratory findings suggestive of infection that are usually seen in non-neutropenic patients cannot be used to exclude the possibility of infection. Therefore, absence of abnormalities, such as cerebrospinal fluid (CSF) pleocytosis, pyuria, or neutrophils on sputum Gram stain, does not rule out infection.

Serum fungal markers — Checking fungal markers from the serum, such as the Aspergillus galactomannan antigen and the beta-D-glucan assay, should also be considered in high-risk patients. Fungal markers are checked starting with onset of neutropenia and continued until neutrophil recovery. They are not routinely sent in low-risk patients except as part of an evaluation for suspected fungal infection. Some centers perform serial monitoring of these twice weekly in hematopoietic cell transplant recipients and acute leukemia patients not receiving anti-mold prophylaxis, where a positive test may guide further evaluation or prompt pre-emptive therapy [2]. In patients receiving an agent with antimold activity, the value of this approach has not been established. The Aspergillus galactomannan antigen is a specific test for invasive aspergillosis, whereas the beta-D-glucan assay is a nonspecific test for several invasive fungal infections, including aspergillosis and candidiasis. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay' and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Beta-D-glucan assay'.)

Microbiology and other diagnostic testing — In all cancer patients presenting with neutropenic fever, empiric antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed. The microbiologic evaluation should be performed promptly. (See 'Initiation of empiric therapy' below.)

Specimens for the microbiology laboratory should include at least two sets of blood cultures (table 1) [2]. Each set should have a volume of 20 mL (proportionally smaller volume in children weighing <40 kg; eg, no more than 1 percent of estimated patient total blood volume). In patients with a CVC, we prefer to collect a set of blood cultures simultaneously from each lumen and from a peripheral vein site. Some experts feel that it is acceptable to collect both sets of cultures from the CVC, especially in patients with difficult peripheral venous access. In patients without a CVC, a set should be obtained from each of two separate venipuncture sites. The diagnosis of CVC infections is discussed in greater detail separately. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis".)

Two sets of blood cultures are typically repeated daily for persistent fevers or rigors at least during the first two days following initiation of empiric antibiotics [2]. Institutions may have different guidelines for the frequency of obtaining blood cultures. As an example, some centers stop collecting blood cultures or reduce the frequency of collection after several days if the initial cultures are negative for patients with a stable fever pattern. If the cultures are positive, they should be repeated until they become negative to ensure response to therapy and intermittently thereafter.

Specimens should be obtained from other sites as clinically indicated (eg, sputum, urine, CVC exit site, CSF, skin, stool). Many neutropenic patients receiving cytotoxic chemotherapy are also thrombocytopenic; in such patients, platelet transfusions are often necessary in order to safely perform a lumbar puncture or other invasive procedures. In general, indications for collection of these additional samples are as follows [2]:

Stool – If diarrhea is present, send a C. difficile toxin assay. There is limited utility in sending stool samples for culture or ova and parasites in hospitalized patients in the United States; these studies can be sent in patients with recent travel to or residence in areas that are endemic for enteric pathogens or if there is another reason to suspect an enteric pathogen. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Urine – If symptoms of urinary tract infection are present, send urine for bacterial culture and susceptibility testing. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults".)

Skin – If skin lesions are present, aspirate or biopsy lesions for bacterial and fungal stains and cultures, and, if vesicles are present, send for either herpes simplex virus and varicella-zoster virus polymerase chain reactions (PCRs) or culture plus direct fluorescent antibody testing. When a biopsy is obtained, it should also be sent for histopathology. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis' and "Diagnosis of varicella-zoster virus infection".)

Respiratory – If productive cough is present, send sputum for bacterial and fungal stains and cultures and assays for respiratory viruses [6]. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

Neutropenic patients with pulmonary infiltrates often cannot produce sputum; a more invasive approach, including bronchoscopy with bronchoalveolar lavage (table 3) or video-assisted thoracoscopic surgery, may need to be pursued in order to make a microbiologic diagnosis. This may be particularly important for patients with infiltrates on chest radiographs or chest computed tomography (CT) who continue to worsen despite 24 to 48 hours of empiric antibiotic therapy. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

In patients with an influenza-like illness (especially when respiratory viruses are circulating), a nasopharyngeal swab should be sent for influenza testing (ideally with a molecular test, such as PCR), as well as testing for other respiratory viruses (respiratory syncytial virus, adenovirus, parainfluenza virus, human metapneumovirus). (See "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Laboratory confirmation' and "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Diagnostic tests of choice for different adenovirus syndromes' and "Human metapneumovirus infections", section on 'Diagnosis' and "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Testing for coronavirus disease 2019 (COVID-19) is also discussed separately. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

Cerebrospinal fluid – If symptoms of meningitis (fever, headache, nuchal rigidity, altered mental status) are present, send CSF for cell count, glucose, protein, and bacterial culture and susceptibility testing. In addition, in patients with clinical signs of meningitis and/or encephalitis, CSF should also be sent for cryptococcal antigen testing and for PCR testing for herpes simplex virus, cytomegalovirus, varicella-zoster virus, and, in allogeneic hematopoietic cell transplant recipients, human herpesvirus 6. Additional tests are indicated if epidemiologic risk factors are present (eg, testing for West Nile virus, Eastern equine encephalitis, and other arthropod-borne encephalitides during the summer in certain regions). (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Cerebrospinal fluid examination' and "Aseptic meningitis in adults" and "Herpes simplex virus type 1 encephalitis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV" and "Arthropod-borne encephalitides" and "Overview of diagnostic tests for cytomegalovirus infection" and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Diagnosis'.)

Imaging — Imaging studies should be performed promptly but should not delay initiation of empiric therapy. (See 'Initiation of empiric therapy' below.)

In febrile neutropenic patients with respiratory signs or symptoms, we suggest that a chest radiograph be obtained in low-risk patients and a noncontrast intermediate- or high-resolution chest CT be obtained in high-risk patients (see 'Risk assessment' above). In contrast, the Infectious Diseases Society of America guidelines recommend a chest radiograph as part of the initial evaluation for neutropenic fever in patients with respiratory symptoms without distinction by risk status [2]. It is important to note, however, that chest radiograph findings are often minimal or absent, even in patients with pneumonia or pulmonary nodules. Intermediate- or high-resolution chest CT is much more sensitive for detecting abnormalities in neutropenic patients. One should be mindful that detection of small nodules may represent benign granulomas in certain areas endemic for certain infections rather than active infection, and therefore caution in interpretation should be exercised.

In one study, high-resolution chest CT demonstrated pneumonia in more than one-half of persistently febrile neutropenic patients who had normal findings on routine chest radiograph [7]. It was estimated that high-resolution CT scanning resulted in the diagnosis being established five days earlier compared with the exclusive use of chest radiographs but did not improve clinical outcomes. Although CT scanning has not been shown to change clinical outcomes, one should have a low threshold for ordering a CT scan in both high- and low-risk neutropenic patients with pulmonary symptoms to help guide the selection and duration of treatment and to assess for radiographic evidence of invasive fungal disease. Repeat chest imaging should be obtained for increasing or persistent pulmonary symptoms and signs, including cough, shortness of breath, and/or hypoxia [2]. Radiographic findings may become evident along with an increase in symptoms as the neutropenia begins to resolve.

CT scanning of other sites (head, sinuses, abdomen/pelvis) should be performed according to suggestive symptoms or other risk factors [2]. In particular, patients with neutropenic fever and any signs or symptoms suggestive of neutropenic enterocolitis or C. difficile colitis (eg, abdominal pain or tenderness, diarrhea) should undergo abdominal CT scanning with IV and oral contrast. (See "Neutropenic enterocolitis (typhlitis)", section on 'Diagnosis' and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)

INITIATION OF EMPIRIC THERAPY — Fever in a neutropenic patient should be considered a medical emergency (algorithm 1). Early studies documented mortality rates of up to 70 percent if initiation of antibiotics was delayed [8]. Therefore, the evaluation of such patients should occur promptly, and broad-spectrum antibiotics should be given as soon as possible (within 60 minutes of presentation) and at full doses (adjusted for renal and/or hepatic function). In all cancer patients presenting with neutropenic fever, empiric antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed. (See "Overview of neutropenic fever syndromes", section on 'Timing of antibiotics'.)

The aim of empiric therapy is to cover the most likely and most virulent pathogens that may rapidly cause serious or life-threatening infection in neutropenic patients [2]. Empiric therapy approaches are discussed separately. (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".)

EVALUATION OF PERSISTENT OR RECURRENT FEVER — Persistent or recurrent fever should prompt a thorough search for a source of occult infection. Repeat cultures of blood and other cultures or diagnostic tests should be performed on the basis of symptoms and signs. Diarrhea should be evaluated with a C. difficile toxin assay.

Repeating and/or broadening the imaging evaluation is warranted for persistent or recurrent fever. An abdominal computed tomography (CT) scan should be considered to evaluate for neutropenic enterocolitis when abdominal signs are present (see "Neutropenic enterocolitis (typhlitis)"). CT scans of the chest and sinuses are useful to evaluate for occult mold infections. (See "Diagnosis of invasive aspergillosis", section on 'Imaging' and "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Imaging' and "Mucormycosis (zygomycosis)" and "Fungal rhinosinusitis".)

Management algorithms have been developed for the reassessment of neutropenic patients with persistent fever after two to four days (algorithm 2) and after four or more days (algorithm 3) [2]. The risk assessment and management of patients with neutropenic fever is discussed in detail separately. (See "Risk assessment of adults with chemotherapy-induced neutropenia" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Persistent fever' and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

The diagnosis and management of sepsis syndromes are also discussed separately. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Evaluation and management of suspected sepsis and septic shock in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neutropenic fever in adults with cancer".)

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 5th to 6th 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 10th to 12th 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 email 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

Fever during chemotherapy-induced neutropenia is a medical emergency requiring prompt evaluation and treatment. Fever in neutropenic patients is defined as a single oral temperature of >38.3°C (101.0°F) or a temperature of >38.0°C (100.4°F) sustained for >1 hour. We define severe neutropenia as an absolute neutrophil count <500 cells/microL. (See 'Introduction' above and 'Fever' above and 'Neutropenia' above.)

In all cancer patients presenting with neutropenic fever, empiric antibacterial therapy should be initiated as soon as possible (within 60 minutes of presentation), immediately after blood cultures have been obtained, and before any other investigations have been completed (algorithm 1). (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".)

Bacteremia is documented in only 10 to 25 percent of neutropenic fever episodes, and clinically documented infections are found in 20 to 30 percent. Most documented infections during neutropenia are due to gram-positive organisms. Fungi and viruses can also be pathogens, particularly in high-risk patients. (See 'Microbiology' above.)

The diagnostic evaluation should include a targeted history, physical examination, and laboratory assessments (table 1). This includes:

Blood cultures and cultures obtained from other suspected sites of infection.

Chest imaging – In febrile neutropenic patients with respiratory signs or symptoms, we suggest that a chest radiograph be obtained in low-risk patients and a chest computed tomography (CT) scan be obtained in high-risk patients.

Abdominal imaging – Patients with neutropenic fever and any signs or symptoms suggestive of neutropenic enterocolitis or Clostridioides difficile colitis (eg, abdominal pain or tenderness, diarrhea) should undergo abdominal CT scanning. (See 'Patient evaluation' above.)

Persistent or recurrent fever should prompt a thorough search for a source of occult infection. Repeat cultures of blood and other cultures or diagnostic tests should be performed on the basis of symptoms and signs. Management algorithms have been developed for the reassessment of neutropenic patients with persistent fever after two to four days (algorithm 2) and after four or more days (algorithm 3). (See 'Evaluation of persistent or recurrent fever' above.)

ACKNOWLEDGEMENTS — The UpToDate editorial staff acknowledges Dr. Gregory K Robbins and Dr. Kieren A Marr, who contributed to earlier versions of this topic review.

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  2. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56.
  3. Zuckermann J, Moreira LB, Stoll P, et al. Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes. Ann Hematol 2008; 87:139.
  4. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol 2018; 36:1443.
  5. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm (Accessed on December 08, 2020).
  6. Hirsch HH, Martino R, Ward KN, et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis 2013; 56:258.
  7. Heussel CP, Kauczor HU, Heussel GE, et al. Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography. J Clin Oncol 1999; 17:796.
  8. Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med 1971; 284:1061.
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