Risk Factors For Neutropenic Fever Health And Social Care Essay

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1st Jan 1970 Health And Social Care Reference this

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Cancer patients, who receive cytotoxic antineoplastic therapy sufficient to harmfully affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa, are at high risk for invasive infection due to the translocation of colonizing bacteria and/or fungi across intestinal mucosal surfaces.

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Since the level of the neutrophil-mediated component of the inflammatory response are typically attenuated in neutropenic patients 1, physical findings of exudate, fluctuation, ulceration or fissure, local heat, swelling, and regional adenopathy are all less prevalent in the neutropenic patient1. Thus, fever might be the earliest and only sign of a severe underlying infection 2.

With the increasing use of myelo-suppressive agents in the treatment of neoplastic and nonneoplastic diseases, the increased rate of infection in patients with neutropenia has been clearly established 3. Sadly, many of these commonly fatal infections go unrecognized until autopsy 4.

Therefore, in order to avoid unfortunate outcomes such as sepsis and possibily death, it is critical to recognize neutropenic fever early and to start empiric systemic antibacterial therapy promptly. It is also crucial to assess the risk of serious complications in patients with febrile neutropenia, since this assessment will dictate the approach to therapy, including the need for inpatient admission, IV antibiotics, and prolonged hospitalization 2.

An overview of the concepts related to neutropenic fever, including definitions of fever and neutropenia and categories of risk are reviewed here.

The risk assessment and the diagnostic approach to patients presenting with febrile neutropenia are also discussed.

This topic also provides a general approach to the management of neutropenic fever syndromes in cancer patients at high and low risk for complications, and the prophylaxis of infections in such patients.

DEFINITIONS

Fever:

The definition of fever as an indicator of infection in patients with neutropenia has varied. Carl Wunderlich proposed in 1868, that the mean normal body temperature was 37¿½C (98.6¿½F) with an upper limit of normal of 38¿½C (100.4¿½F), above this limit, fever was defined 5,6.

Although it has been observed that there is a range of normal body temperatures, according to a survey of 270 medical professionals, 75 percent of subjects reported that normal body temperature is 37¿½C (98.6¿½F)5,7.

While, a survey of members of the British Society for Hematology concerning their institutional definitions of fever identified ten definitions of fever, ranging from a single temperature >37.5¿½C to either a single temperature >39¿½C or two successive temperatures >38.4¿½C 5,6.

Despite these beliefs, the mean oral temperature was reported as 36.8¿½0.4¿½C (98.2¿½0.7¿½F) with a range of 35.6¿½C (96.0¿½F) to 38.2¿½C (100.8¿½F), after observation of 148 healthy adults ages between 18 and 40 years 6.

The definition of fever in neutropenic patients, according to The Infectious Diseases Society of America, was proposed as a single oral temperature of >38.3¿½C (101¿½F) or a temperature of >38.0¿½C (100.4¿½F) sustained for >1 hour2. Similar definitions have been provided from South America, Europe, and Asia. It has been approved to use this definition of fever in neutropenic patients9¿½11.

Neutropenia:

The definition of neutropenia differs from institution to institution, but it is usually defined as an absolute neutrophil count (ANC) <1500 cells/microL.

The absolute neutrophil count (ANC) is defined as the product of the white blood cell count (WBC) and the percentage of polymorphonuclear cells (PMNs) and bands:

ANC = WBC (cells/microL) x percent (PMNs + bands) ¿½ 100

Based upon the level of ANC, neutropenia is categorized as mild, moderate or severe. An absolute neutrophil count between 1000 and 1500/microL corresponds to mild neutropenia. While, an ANC between 500 and 1000/microL corresponds to moderate neutropenia. Severe neutropenia is usually defined as an ANC <500 cells/microL, or an ANC that is expected to drop to <500 cells/microL over the next 48 hours2.

As the neutrophil count drops below 500 cells/microL, the risk of clinically serious infection increases and is higher in those with a prolonged duration of neutropenia (>7 days). However, the risk is also related to the adequacy of the marrow reserve pool of granulocytes.

Two terms, leukopenia and granulocytopenia are often used interchangeably with neutropenia, although they are somewhat different:

¿½ Leukopenia is defined as a low total white blood cell count that may be due to any cause such as lymphopenia and/or neutropenia; yet, almost all leukopenic patients are neutropenic since the amount of neutrophils is so much higher than the amount of lymphocytes.

¿½ Granulocytopenia is defined as a reduced absolute number of all circulating cells of the granulocyte series (neutrophils, eosinophils, and basophils); yet, almost all granulocytopenic patients are neutropenic since the amount of neutrophils is so much higher than the amount of eosinophils and basophils.

¿½ Agranulocytosis is defined as the absence of granulocytes, but the term is often inaccurately used to denote severe neutropenia.

CATEGORIES OF RISK

RISK FACTORS FOR NEUTROPENIC FEVER

The risk factors for the development of neutropenic fever can be divided into three sub-categories including patient-related, disease-related and anti-cancer treatment-related predictors.

Patient-related predictors include: age = 65 years, female sex, high body surface area, poor performance status based upon preexisting active comorbidities (e.g., cardiovascular, pulmonary, renal, endocrine, etc.) and poor nutritional status12¿½19.

Disease-related predictors include: Elevated lactate dehydrogenase (LDH) in patients with lymphoreticular diseases, bone marrow failure due to replacement of hematopoietic tissue by anomalous tissue which is know as myelophthisis19, lymphopenia20,21 and advanced stage of the underlying malignancy 13,16,20¿½22

Treatment-related predictors include: administration of the planned dose-intensity of high-dose chemotherapy regimens15,20¿½23 and failure to administer prophylactic hematopoietic growth factor support to patients receiving high-risk regimens14,21.

RISK OF SERIOUS COMPLICATIONS

This risk assessment is essential to determine the management of patients, including the need for inpatient admission, IV antibiotics, and prolonged hospitalization. High-risk patients require hospital admission for IV antibiotics, and often a prolonged length of stay. In contrast, low-risk patients may be treated as outpatients with oral antibiotic after a short period of observation or hospitalization.

Definitions of low-risk and high-risk patients:

The Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) use different definitions in their guidelines:

¿½ Low-risk patients are those who are expected to have neutropenia (absolute neutrophil count [ANC] <500 cells/microL) for =7 days, those with no comorbidities or evidence of significant hepatic or renal dysfunction2, and most patients receiving chemotherapy for solid tumors. This group has been considered to be at low-risk for complications requiring hospitalization or prolonging hospitalization after being well studied by randomized trials.

¿½ High-risk patients are those expected to have neutropenia (ANC <500 cells / microliter) for > 7 days. While, neutropenic febrile patients with comorbidities or evidence of significant hepatic or renal impairment are considered high risk, regardless of the duration of neutropenia. Some experts have identified patients at high risk as those who are expected to have profound neutropenia (ANC = 100 cells / microliter) for > 7 days on the basis of experience that these patients are more likely to have serious and potentially fatal complications2,24. Nevertheless, formal studies to clearly differentiate between patients with a neutrophil count <500 cells / microliter and = 100 cells / microliter are missing.

Some studies combine these groups to define high-risk patients. Deep prolonged neutropenia (ANC = 100 cells / microL expected to last > 7 days) is more likely to occur in the pre-transplant hematopoietic cell transplantation (allogeneic in particular) and in patients undergoing induction chemotherapy for acute leukemia.

Risk based on underlying disease

Patients who suffer from neutropenia after induction chemotherapy for acute myelogenous leukemia or as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) are at a high-risk for serious infections.

Other factors that are considered as high-risk status include gastrointestinal and oral mucositis, uncontrolled cancer, chronic obstructive pulmonary disease, advanced age and poor functional status.

Patients receiving consolidation chemotherapy for leukemia or undergoing autologous HCT may also have long periods of neutropenia, but seem to be at somewhat lower risk, especially if they received prophylactic hematopoietic growth factors.

In contrast, patients with solid tumors are mostly at low risk for serious infections.

Guidelines

An assessment of risk (high versus low-risk) for medical complications related to neutropenic fever should be obtained at the initial assessment of neutropenic fever episode. The Infectious Diseases Society of America (IDSA), the European Society for Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN) as well as the American Society of Clinical Oncology (ASCO)2,24,25 , has recommended this.

The IDSA and ASCO defined high-risk neutropenic patients as those who are expected to have profound neutropenia (ANC = 100 cells / microliter) for > 7 days or those with evidence of current comorbidities or hepatic or renal dysfunction2,24 . The National Comprehensive Cancer Network (NCCN) has used similar criteria for definition, but also includes a category of intermediate risk [21].

Multinational Association of Supportive Care in Cancer (MASCC) risk index that can be used as an alternative to clinical criteria, is a validated tool to assess the risk of medical complications associated with neutropenic fever (calculator 2)26¿½29 .

IDSA Risk assessment:

The Infectious Diseases Society of America (IDSA) has established the following criteria for the definition of high risk or low risk patients with neutropenic fever 2:

High-risk febrile neutropenic patients are defined as having one or more of the following criteria:

? Profound neutropenia (ANC = 100 cells / microliter) expected to last for > 7 days.

? Proof of current comorbidities, such as (but not limited to):

? Hemodynamic instability

? Oral mucositis limiting swallowing or gastrointestinal tract mucositis causing severe diarrhea

? Gastrointestinal symptoms such as abdominal pain, nausea and vomiting or diarrhea

? Changes in neurological status or mental appearance of new onset

? Intravascular catheter infection

? New pulmonary infiltrates or hypoxia

? Underlying chronic lung disease

? Signs of hepatic insufficiency (serum transaminase> 5 times normal) or renal insufficiency (creatinine clearance <30 mL / min)2

Low-risk febrile neutropenic patients are expected to have a relatively short duration of neutropenia for 7 days or less, with an absolute neutrophil count (ANC) <500 cells / microliter and have no comorbidities or evidence of significant hepatic or renal impairment2 . In addition, most patients taking chemotherapy for solid tumors are considered at low-risk for complications.

Patients with evidence of severe sepsis (sepsis syndrome in end organ dysfunction) should be considered at high risk and managed as in-patients with initial intravenous antibacterial empirical treatment. While, patients with signs of septic shock should be managed in an intensive care unit based upon goal-oriented therapy30 .

NCCN risk assessment

The National Comprehensive Cancer Network (NCCN) has developed certain criteria to classify patients as high risk or low risk, which must be performed during the initial evaluation [21].

High-risk febrile neutropenic patients are those having one or more of the following criteria: [21]

? The patients are hospitalized at the time of the development of fever

? Evidence of significant medical comorbidity or the presence of clinical instability

? Expected profound prolonged neutropenia (ANC = 100 cells / microliter expected to last> 7 days)

? Hepatic insufficiency (serum transaminase> 5 times normal) or renal insufficiency (creatinine clearance <30 mL / min)

? Any patient with leukemia not in complete remission, or any non-leukemic patient with signs of disease progression after more than two courses of chemotherapy.

? Any complex infection such as pneumonia at clinical presentation

? Alemtuzumab (antineoplastic agent) in the last two months

? Grade 3 or 4 mucositis

? MASCC risk index score <21

Low-risk febrile neutropenic patients are those who do not meet any of the criteria for high-risk described above and meet most of the criteria as follows [21]:

? Ambulatory status at the time of the development of fever

? No acute comorbid illness requiring hospitalization and close monitoring

? Expected short duration of severe neutropenia (ANC = 100 cells / microliter should last for 7 days or less)

? Good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1 (Table 2))

? No hepatic or renal insufficiency

? MASCC risk index score of = 21 risk index

Intermediate risk neutropenic patients are defined as those meeting one or more of following criteria: [21]

? Patients undergoing autologous HCT

? Lymphoma

? Chronic lymphocytic leukemia

? Multiple Myeloma

? Patients receiving purine analogue therapy

? The expected duration of neutropenia is 7 to 10 days

For patients at intermediate risk, the NCCN recommends consideration of fluoroquinolone prophylaxis.

Multinational Association of Supportive Care in Cancer (MASCC) score

As an alternative to the IDSA and NCCN risk assessments described above, the MASCC risk index is validated for assessing the risk of medical complications associated with febrile neutropenia.

Using the MASCC risk index, the following features are assessed and given a weighted score2,26 :

? Burden of disease (clinical condition of the patient at the time of presentation with neutropenic fever):

? No symptoms or mild symptoms (5 points)

? Moderate symptoms (3 points)

? Severe symptoms or dying (0 point)

? No hypotension (systolic blood pressure> 90 mmHg) (5 points)

? No chronic obstructive pulmonary disease COPD (4 points)

? Solid tumor or hematologic malignancy without prior history of fungal infections (4 points)

? No dehydration that requires parenteral fluids (3 points)

? Ambulatory status at the time of the onset of neutropenic fever syndrome (3 points)

? Age <60 years (2 points)

The highest possible score is 26.

Patients with a score = 21 are considered to be at low risk of serious medical complications, and for whom outpatient treatment with oral empirical antimicrobial can be safe and effective29 .

While, patients with a score <21 are considered to be at high risk for serious medical complications, and therefore should be treated as inpatients.

The MASCC risk index has classified 98% of patients as low-risk and 86% as high risk with a sensitivity and specificity of 95%, and positive and negative predictive value of 98, and 86 percent, respectively 28.

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Patients with complicated infections have been reclassified as high risk for serious medical complications, which further increased the predictive value of the model. Complicated infections include non-necrotizing skin or soft tissue infection (SSTI) of >5 cm diameter, necrotizing SSTI of any size, grade 2 oral mucositis, sepsis syndrome or the presence of a visceral site of infection. [28]. The classification error rate has been 10 to 29 percent. [4]

In addition, the MASCC risk index can predict the probability of death as follows:27

? Score = 15: 29 %

? Score = 15 but <21: 9 %

? Score = 21: 2 %

The MASCC risk index has been criticized for the lack of a standard definition of this criterion “the burden of febrile neutropenia”, which could be a source of confusion2, or it could be interpreted differently by different clinicians. I addition, the MASCC risk index does not include the duration of neutropenia as a criterion, though it is considered as an important predictor of risk2.

The MASCC risk index has been also criticized because it was developed using heterogeneous patient populations; thus, it might not function optimally in all populations. For example, in a retrospective study of patients with solid tumors who seemed to be clinically stable, the MASCC risk index had a low sensitivity to detect complications (36 percent)31. The low sensitivity was likely to be attributed to the fact that patients were all outpatients, and the rates of hypotension, dehydration and invasive fungal infections were low; hence, only three criteria were present to distinguish prognosis.

The serious medical complications are provided by the MASCC risk index as follows 26:

? Hypotension defined as systolic blood pressure <90 mmHg or the need for vasopressor support to maintain blood pressure

? Respiratory failure defined as arterial oxygen pressure <60 mmHg on room air or the need for mechanical ventilation

? The admission to ICU

? Disseminated intravascular coagulation

? Presence of confusion, delirium, or altered mental status

? The development of congestive heart failure documented by chest imaging and requiring treatment

? Bleeding diathesis sufficient to require a blood transfusion

? Electrocardiogram changes or arrhythmias requiring treatment

? Renal failure sufficient to require an investigation and / or treatment with IV fluids, dialysis, or other intervention

? Other complications judged serious and clinically significant by the health care team

All patients who were treated with systemic antineoplastic therapy six weeks prior to a systemic inflammatory response syndrome (SIRS) are assumed to have neutropenic sepsis syndrome until proven otherwise. SIRS is defined by the presence of two or more of the following conditions: temperature >38¿½C or <36¿½C, heart rate> 90/minute, respiratory frequency > 20/minute, PaCO2 <32 mmHg32.

Patients presenting with altered mental status, hypotension, hypoxia, oliguria or any other sign of new organ impairment must be managed emergently for severe sepsis.

RISK OF TREATMENT FAILURE

The risk of failure to respond to initial empirical antibacterial therapy is a composite outcome to be considered clinicians. Treatment failure is proposed if one or more of the following events occur within 30 days after the start of treatment 33,34:

? Persistence, progression or recurrence of signs of infection

? Modification of the initial empirical antibacterial treatment

? Readmission to the hospital for outpatients

? Death

Patients with documented clinical or microbiological infections are more likely to be at risk for treatment failure, clinical or microbiological than for unexplained neutropenic fever (39 against 18 percent33.

High-risk patients are more likely to be at risk for treatment failure than those with low risk. For example, patients with hematologic malignancies have a higher percentage of treatment failure than those with solid tumors (44 against 18 percent) 33.

Observations have shown that among all febrile neutropenic patients at low risk of medical complications, adult patients at higher risk for treatment failure than children with 16% against 5% respectively34.

PREVENTION

In order to prevent neutropenic fever and infectious complications in patients at increased risk, the administration of an antimicrobial drug should be used as a prophylaxis.

Antibacterial prophylaxis

Pseudomonas aeruginosa and other gram-negative bacilli is the target of the antibacterial prophylaxis, because these pathogens are virulent and may cause life-threatening infections.

INDICATIONS

The beneficial effect on clinical outcomes has been sought from the administration of prophylactic antibacterial agents. The fluoroquinolones, levofloxacin (500 mg orally once daily) and ciprofloxacin (500 mg orally twice daily) have been the most studied antibacterial agents. Levofloxacin in particular is preferred in patients at increased risk for oral mucositis-related Streptococcus viridans infection 2. Results have been mixed with respect to effectiveness and have incited concern about toxicities and antibacterial resistance35¿½37. A systematic monitoring of the prevalence of fluoroquinolone resistance among gram-negative bacilli should be done, at the intitutions that use fluoroquinolone prophylaxis.

Based upon the available data, high-risk neutropenic patients defined by those who are expected to have an absolute neutrophil count <500 cells/microL for more than 7 days and who do not have a contraindication to receiving a fluoroquinolone, are recommended to receive fluoriquinolone prophylaxis. While, intermediate-risk patients are sometimes given an antibacterial prophylaxis, a decision made on a case-by-case basis.

Fluoroquinolone should be used with caution in patients at risk of a prolonged QT interval particularly in those who may require other QT prolonging agents, such as voriconazole.

In addition, the potential to promote resistance among gram-negative and gram-positive should be considered when deciding whether to give a fluoroquinolone prophylaxis or not37. Concerns about the possibility of increasing the risk of Clostridium difficile infection has also been present, though this has not been proven in neutropenic patients receiving fluoroquinolone prophylaxis37. The use of prophylactic agents in institutions and geographic areas where the levels of resistance to fluoroquinolones are high is less likely to be efficient36,38.The use of antibacterial prophylaxis varies from one center to another with some centers avoiding such practices.

For most patients with chemotherapy-induced neutropenia expected to be of short duration particularly patients with solid tumors, the use of antibacterial prophylaxis is not recommended.

TIMING

The ideal timing for the initiation and cessation antibacterial prophylaxis has not been sufficiently studied2. Many clinicians begin anti-bacterial prophylaxis, the first day of chemotherapy or the day after the administration of the last dose of chemotherapy cycle. Antibacterial prophylaxis is usually withheld when neutropenia resolves, or when empirical antibacterial regimen is initiated for patients who become febrile during neutropenia.

Antifungal prophylaxis

Among cancer patients and HCT recipients, a high rate of life-threatening invasive fungal infections such as candidemia has been observed since the late 1980s, which incited interest in antifungal prophylaxis for patients receiving chemotherapy.

Antiviral prophylaxis

INFLUENZA

Annual immunization with an inactivated influenza vaccine is recommended for all cancer patients undergoing treatment2. The influenza vaccine is generally administered >2 weeks before the initiation of chemotherapy or, when circumstances dictate, between chemotherapy cycles and at least seven days after the last cycle. However, the best timing for such immunization has not been established2. All family members and other close contacts should get annual immunization too.

HSV and VZV

Reactivation of herpes simplex virus (HSV-1 and HSV-2) and varicella-zoster virus (VZV) occur commonly in HCT recipients who are not receiving prophylaxis and are important causes of morbidity. However, reactivation of both HSV and VZV infections can be effectively prevented with antiviral prophylaxis.

Antiviral prophylaxis with acyclovir (400 mg orally three to four times daily or 800 mg orally twice daily) or valacyclovir (500 mg orally once or twice daily) is recommended in all patients who are seropositive for HSV and who are undergoing allogeneic HCT or induction chemotherapy for acute leukemia39. Antiviral prophylaxis with acyclovir or valacyclovir is also recommended in all HCT recipients who are seropositive for VZV. Based upon randomized trials, benefits of antiviral prophylaxis in these populations have been demonstrated; thus, recommended41.

CMV

CMV prophylaxis is indicated for HCT recipients because they are at are at significant risk for reactivation. In contrast, prophylaxis is not indicated in patients with chemotherapy-induced neutropenia, because it does not occur commonly.

HEPATITIS B

Antiviral prophylaxis should be considered for the following categories of patients and should be sustained for at least six months after the completion of chemotherapy40 :

? Patients receiving chemotherapy who have a previous history of hepatitis B virus infection, due to the risk of reactivation and hepatic failure.

? Patients with elevated circulating hepatitis B DNA or detectable levels of circulating hepatitis B surface antigen (HBsAg)

? Patients with a previous history of infection with detectable levels of antibody to HBsAg or to hepatitis B core antigen.

This has been demonstrated to be able to reduce the risk of reactivation from 24 to 53 percent to 0 to 5 percent.

Colony stimulating factors

Granulocyte colony stimulating factors (CSFs) have been widely evaluated for prophylactic use following the administration of intensive cytotoxic chemotherapy when neutropenia is expected (primary prophylaxis). CSFs have been also evaluated for their prophylactic use during retreatment after a previous cycle of chemotherapy that caused neutropenic fever (secondary prophylaxis), and have been shown to minimize the extent and duration of severe chemotherapy-induced neutropenia in afebrile patients (afebrile neutropenia). Their use is not recommended in febrile chemotherapy-induced neutropenia2. However, prophylactic use of granulocyte CSFs has not been shown to have an effect on survival in most clinical situations.

PRIMARY PROPHYLAXIS

Primary prophylaxis denotes the use of granulocyte CSFs during the first cycle of myelosuppressive chemotherapy in order to prevent neutropenic complications. The goal of primary prophylaxis is to decrease the incidence of neutropenic fever and the need for hospitalization, to maintain dose-dense or dose-intense chemotherapy strategies that have survival benefits.

Updated 2010 guidelines from the European Organization for Research and Treatment of Cancer (EORTC), the Infectious Diseases Society of America (IDSA), consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), and The 2006 guidelines from the American Society of Clinical Oncology (ASCO), all recommend primary prophylaxis when the expected incidence of neutropenic fever is over 20 percent, to reduce the need for hospitalization for antibiotic therapy2,22,41. These recommendations are based upon randomized trials that have shown that primary prophylaxis was cost effective when the risk of neutropenic fever with a specific regimen was over 20 percent42,43 .

In contrast, guidelines recommend against the routine use of granulocyte CSFs for primary prophylaxis in adult patients receiving chemotherapy regimens with an anticipated low probability (<10 percent) of neutropenic fever2,22,41 .

However, when the anticipated risk of neutropenic fever is between 10 and 20 percent, the decision of primary prophylaxis should be individualized and may be appropriate in a number of clinical settings in which patients are at risk or increased complications22,41 :

¿½ Age >65 years

¿½ Preexisting neutropenia

¿½ More advanced cancer

¿½ Poor performance and/or nutritional status

¿½ Renal or hepatic impairment

¿½ In the case of epithelial ovarian cancer

¿½ Extensive prechemotherapy surgery, particularly if it included a bowel resection.

In patients receiving concomitant chemoradiotherapy for either head and neck cancer or lung cancer, the use of granulocyte CSFs has been associated with adverse outcomes, therefore, it better be avoided.

Despite the lack of comparative data from randomized controlled trials, that could recommend one CSF over the other for prophylaxis of infection during chemotherapy-induced neutropenia, in practice, most institutions use G-CSF.

SECONDARY PROPHYLAXIS

Secondary prophylaxis denotes to the use of a granulocyte CSF in subsequent chemotherapy cycles after a prior cycle has caused neutropenic fever. Secondary prophylaxis with CSFs reduces the risk of reccurence of neutropenic fever by approximately one-half 44.

ASCO and EORTC guidelines recommend that secondary prophylaxis with granulocyte CSFs be limited to patients for whom primary prophylaxis was not given and who experience a neutropenic complication from a prior cycle of chemotherapy if neutropenic fever would prevent the administration of full dose chemotherapy and if reduced dose intensity might affect treatment outcome22,41 .

TIMING

G-CSF and GM-CSF therapy is usually initiated 24 to 72 hours after cessation of chemotherapy and is frequently continued until the absolute neutrophil count reaches 5000 to 10,000/microL. A reasonable alternative is continuation until clinically adequate neutrophil recovery.

MANAGEMENT

Initial Assessment

Since, fever might be the first and only sign of infection in a neutropenic patient, its occurrence should be considered a medical emergency. Therefore, empiric broad-spectrum antibacterial therapy should be started immediately after blood cultures have been obtained and before any other investigations have been completed. The Infectious Diseases Working Party of the German Society of Hematology and Oncology and the Northern Ireland Cancer Network has recommended this.

It has been recommended that empiric broad-spectrum antibacterial therapy should be administered within 60 minutes of presentation for all patients suffering from neutropenic fever at presentation. (algorithm 1)

Diagnostic Approach

At presentation, a detailed history and physical examination should be done, as well as a complete laboratory, microbiologic and imaging work-up for all febrile neutropenic patients.

The table below summarizes the diagnostic approach to patients with febrile neutropenia.

Cancer patients, who receive cytotoxic antineoplastic therapy sufficient to harmfully affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa, are at high risk for invasive infection due to the translocation of colonizing bacteria and/or fungi across intestinal mucosal surfaces.

Since the level of the neutrophil-mediated component of the inflammatory response are typically attenuated in neutropenic patients 1, physical findings of exudate, fluctuation, ulceration or fissure, local heat, swelling, and regional adenopathy are all less prevalent in the neutropenic patient1. Thus, fever might be the earliest and only sign of a severe underlying infection 2.

With the increasing use of myelo-suppressive agents in the treatment of neoplastic and nonneoplastic diseases, the increased rate of infection in patients with neutropenia has been clearly established 3. Sadly, many of these commonly fatal infections go unrecognized until autopsy 4.

Therefore, in order to avoid unfortunate outcomes such as sepsis and possibily death, it is critical to recognize neutropenic fever early and to start empiric systemic antibacterial therapy promptly. It is also crucial to assess the risk of serious complications in patients with febrile neutropenia, since this assessment will dictate the approach to therapy, including the need for inpatient admission, IV antibiotics, and prolonged hospitalization 2.

An overview of the concepts related to neutropenic fever, including definitions of fever and neutropenia and categories of risk are reviewed here.

The risk assessment and the diagnostic approach to patients presenting with febrile neutropenia are also discussed.

This topic also provides a general approach to the management of neutropenic fever syndromes in cancer patients at high and low risk for complications, and the prophylaxis of infections in such patients.

DEFINITIONS

Fever:

The definition of fever as an indicator of infection in patients with neutropenia has varied. Carl Wunderlich proposed in 1868, that the mean normal body temperature was 37¿½C (98.6¿½F) with an upper limit of normal of 38¿½C (100.4¿½F), above this limit, fever was defined 5,6.

Although it has been observed that there is a range of normal body temperatures, according to a survey of 270 medical professionals, 75 percent of subjects reported that normal body temperature is 37¿½C (98.6¿½F)5,7.

While, a survey of members of the British Society for Hematology concerning their institutional definitions of fever identified ten definitions of fever, ranging from a single temperature >37.5¿½C to either a single temperature >39¿½C or two successive temperatures >38.4¿½C 5,6.

Despite these beliefs, the mean oral temperature was reported as 36.8¿½0.4¿½C (98.2¿½0.7¿½F) with a range of 35.6¿½C (96.0¿½F) to 38.2¿½C (100.8¿½F), after observation of 148 healthy adults ages between 18 and 40 years 6.

The definition of fever in neutropenic patients, according to The Infectious Diseases Society of America, was proposed as a single oral temperature of >38.3¿½C (101¿½F) or a temperature of >38.0¿½C (100.4¿½F) sustained for >1 hour2. Similar definitions have been provided from South America, Europe, and Asia. It has been approved to use this definition of fever in neutropenic patients9¿½11.

Neutropenia:

The definition of neutropenia differs from institution to institution, but it is usually defined as an absolute neutrophil count (ANC) <1500 cells/microL.

The absolute neutrophil count (ANC) is defined as the product of the white blood cell count (WBC) and the percentage of polymorphonuclear cells (PMNs) and bands:

ANC = WBC (cells/microL) x percent (PMNs + bands) ¿½ 100

Based upon the level of ANC, neutropenia is categorized as mild, moderate or severe. An absolute neutrophil count between 1000 and 1500/microL corresponds to mild neutropenia. While, an ANC between 500 and 1000/microL corresponds to moderate neutropenia. Severe neutropenia is usually defined as an ANC <500 cells/microL, or an ANC that is expected to drop to <500 cells/microL over the next 48 hours2.

As the neutrophil count drops below 500 cells/microL, the risk of clinically serious infection increases and is higher in those with a prolonged duration of neutropenia (>7 days). However, the risk is also related to the adequacy of the marrow reserve pool of granulocytes.

Two terms, leukopenia and granulocytopenia are often used interchangeably with neutropenia, although they are somewhat different:

¿½ Leukopenia is defined as a low total white blood cell count that may be due to any cause such as lymphopenia and/or neutropenia; yet, almost all leukopenic patients are neutropenic since the amount of neutrophils is so much higher than the amount of lymphocytes.

¿½ Granulocytopenia is defined as a reduced absolute number of all circulating cells of the granulocyte series (neutrophils, eosinophils, and basophils); yet, almost all granulocytopenic patients are neutropenic since the amount of neutrophils is so much higher than the amount of eosinophils and basophils.

¿½ Agranulocytosis is defined as the absence of granulocytes, but the term is often inaccurately used to denote severe neutropenia.

CATEGORIES OF RISK

RISK FACTORS FOR NEUTROPENIC FEVER

The risk factors for the development of neutropenic fever can be divided into three sub-categories including patient-related, disease-related and anti-cancer treatment-related predictors.

Patient-related predictors include: age = 65 years, female sex, high body surface area, poor performance status based upon preexisting active comorbidities (e.g., cardiovascular, pulmonary, renal, endocrine, etc.) and poor nutritional status12¿½19.

Disease-related predictors include: Elevated lactate dehydrogenase (LDH) in patients with lymphoreticular diseases, bone marrow failure due to replacement of hematopoietic tissue by anomalous tissue which is know as myelophthisis19, lymphopenia20,21 and advanced stage of the underlying malignancy 13,16,20¿½22

Treatment-related predictors include: administration of the planned dose-intensity of high-dose chemotherapy regimens15,20¿½23 and failure to administer prophylactic hematopoietic growth factor support to patients receiving high-risk regimens14,21.

RISK OF SERIOUS COMPLICATIONS

This risk assessment is essential to determine the management of patients, including the need for inpatient admission, IV antibiotics, and prolonged hospitalization. High-risk patients require hospital admission for IV antibiotics, and often a prolonged length of stay. In contrast, low-risk patients may be treated as outpatients with oral antibiotic after a short period of observation or hospitalization.

Definitions of low-risk and high-risk patients:

The Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) use different definitions in their guidelines:

¿½ Low-risk patients are those who are expected to have neutropenia (absolute neutrophil count [ANC] <500 cells/microL) for =7 days, those with no comorbidities or evidence of significant hepatic or renal dysfunction2, and most patients receiving chemotherapy for solid tumors. This group has been considered to be at low-risk for complications requiring hospitalization or prolonging hospitalization after being well studied by randomized trials.

¿½ High-risk patients are those expected to have neutropenia (ANC <500 cells / microliter) for > 7 days. While, neutropenic febrile patients with comorbidities or evidence of significant hepatic or renal impairment are considered high risk, regardless of the duration of neutropenia. Some experts have identified patients at high risk as those who are expected to have profound neutropenia (ANC = 100 cells / microliter) for > 7 days on the basis of experience that these patients are more likely to have serious and potentially fatal complications2,24. Nevertheless, formal studies to clearly differentiate between patients with a neutrophil count <500 cells / microliter and = 100 cells / microliter are missing.

Some studies combine these groups to define high-risk patients. Deep prolonged neutropenia (ANC = 100 cells / microL expected to last > 7 days) is more likely to occur in the pre-transplant hematopoietic cell transplantation (allogeneic in particular) and in patients undergoing induction chemotherapy for acute leukemia.

Risk based on underlying disease

Patients who suffer from neutropenia after induction chemotherapy for acute myelogenous leukemia or as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) are at a high-risk for serious infections.

Other factors that are considered as high-risk status include gastrointestinal and oral mucositis, uncontrolled cancer, chronic obstructive pulmonary disease, advanced age and poor functional status.

Patients receiving consolidation chemotherapy for leukemia or undergoing autologous HCT may also have long periods of neutropenia, but seem to be at somewhat lower risk, especially if they received prophylactic hematopoietic growth factors.

In contrast, patients with solid tumors are mostly at low risk for serious infections.

Guidelines

An assessment of risk (high versus low-risk) for medical complications related to neutropenic fever should be obtained at the initial assessment of neutropenic fever episode. The Infectious Diseases Society of America (IDSA), the European Society for Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN) as well as the American Society of Clinical Oncology (ASCO)2,24,25 , has recommended this.

The IDSA and ASCO defined high-risk neutropenic patients as those who are expected to have profound neutropenia (ANC = 100 cells / microliter) for > 7 days or those with evidence of current comorbidities or hepatic or renal dysfunction2,24 . The National Comprehensive Cancer Network (NCCN) has used similar criteria for definition, but also includes a category of intermediate risk [21].

Multinational Association of Supportive Care in Cancer (MASCC) risk index that can be used as an alternative to clinical criteria, is a validated tool to assess the risk of medical complications associated with neutropenic fever (calculator 2)26¿½29 .

IDSA Risk assessment:

The Infectious Diseases Society of America (IDSA) has established the following criteria for the definition of high risk or low risk patients with neutropenic fever 2:

High-risk febrile neutropenic patients are defined as having one or more of the following criteria:

? Profound neutropenia (ANC = 100 cells / microliter) expected to last for > 7 days.

? Proof of current comorbidities, such as (but not limited to):

? Hemodynamic instability

? Oral mucositis limiting swallowing or gastrointestinal tract mucositis causing severe diarrhea

? Gastrointestinal symptoms such as abdominal pain, nausea and vomiting or diarrhea

? Changes in neurological status or mental appearance of new onset

? Intravascular catheter infection

? New pulmonary infiltrates or hypoxia

? Underlying chronic lung disease

? Signs of hepatic insufficiency (serum transaminase> 5 times normal) or renal insufficiency (creatinine clearance <30 mL / min)2

Low-risk febrile neutropenic patients are expected to have a relatively short duration of neutropenia for 7 days or less, with an absolute neutrophil count (ANC) <500 cells / microliter and have no comorbidities or evidence of significant hepatic or renal impairment2 . In addition, most patients taking chemotherapy for solid tumors are considered at low-risk for complications.

Patients with evidence of severe sepsis (sepsis syndrome in end organ dysfunction) should be considered at high risk and managed as in-patients with initial intravenous antibacterial empirical treatment. While, patients with signs of septic shock should be managed in an intensive care unit based upon goal-oriented therapy30 .

NCCN risk assessment

The National Comprehensive Cancer Network (NCCN) has developed certain criteria to classify patients as high risk or low risk, which must be performed during the initial evaluation [21].

High-risk febrile neutropenic patients are those having one or more of the following criteria: [21]

? The patients are hospitalized at the time of the development of fever

? Evidence of significant medical comorbidity or the presence of clinical instability

? Expected profound prolonged neutropenia (ANC = 100 cells / microliter expected to last> 7 days)

? Hepatic insufficiency (serum transaminase> 5 times normal) or renal insufficiency (creatinine clearance <30 mL / min)

? Any patient with leukemia not in complete remission, or any non-leukemic patient with signs of disease progression after more than two courses of chemotherapy.

? Any complex infection such as pneumonia at clinical presentation

? Alemtuzumab (antineoplastic agent) in the last two months

? Grade 3 or 4 mucositis

? MASCC risk index score <21

Low-risk febrile neutropenic patients are those who do not meet any of the criteria for high-risk described above and meet most of the criteria as follows [21]:

? Ambulatory status at the time of the development of fever

? No acute comorbid illness requiring hospitalization and close monitoring

? Expected short duration of severe neutropenia (ANC = 100 cells / microliter should last for 7 days or less)

? Good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1 (Table 2))

? No hepatic or renal insufficiency

? MASCC risk index score of = 21 risk index

Intermediate risk neutropenic patients are defined as those meeting one or more of following criteria: [21]

? Patients undergoing autologous HCT

? Lymphoma

? Chronic lymphocytic leukemia

? Multiple Myeloma

? Patients receiving purine analogue therapy

? The expected duration of neutropenia is 7 to 10 days

For patients at intermediate risk, the NCCN recommends consideration of fluoroquinolone prophylaxis.

Multinational Association of Supportive Care in Cancer (MASCC) score

As an alternative to the IDSA and NCCN risk assessments described above, the MASCC risk index is validated for assessing the risk of medical complications associated with febrile neutropenia.

Using the MASCC risk index, the following features are assessed and given a weighted score2,26 :

? Burden of disease (clinical condition of the patient at the time of presentation with neutropenic fever):

? No symptoms or mild symptoms (5 points)

? Moderate symptoms (3 points)

? Severe symptoms or dying (0 point)

? No hypotension (systolic blood pressure> 90 mmHg) (5 points)

? No chronic obstructive pulmonary disease COPD (4 points)

? Solid tumor or hematologic malignancy without prior history of fungal infections (4 points)

? No dehydration that requires parenteral fluids (3 points)

? Ambulatory status at the time of the onset of neutropenic fever syndrome (3 points)

? Age <60 years (2 points)

The highest possible score is 26.

Patients with a score = 21 are considered to be at low risk of serious medical complications, and for whom outpatient treatment with oral empirical antimicrobial can be safe and effective29 .

While, patients with a score <21 are considered to be at high risk for serious medical complications, and therefore should be treated as inpatients.

The MASCC risk index has classified 98% of patients as low-risk and 86% as high risk with a sensitivity and specificity of 95%, and positive and negative predictive value of 98, and 86 percent, respectively 28.

Patients with complicated infections have been reclassified as high risk for serious medical complications, which further increased the predictive value of the model. Complicated infections include non-necrotizing skin or soft tissue infection (SSTI) of >5 cm diameter, necrotizing SSTI of any size, grade 2 oral mucositis, sepsis syndrome or the presence of a visceral site of infection. [28]. The classification error rate has been 10 to 29 percent. [4]

In addition, the MASCC risk index can predict the probability of death as follows:27

? Score = 15: 29 %

? Score = 15 but <21: 9 %

? Score = 21: 2 %

The MASCC risk index has been criticized for the lack of a standard definition of this criterion “the burden of febrile neutropenia”, which could be a source of confusion2, or it could be interpreted differently by different clinicians. I addition, the MASCC risk index does not include the duration of neutropenia as a criterion, though it is considered as an important predictor of risk2.

The MASCC risk index has been also criticized because it was developed using heterogeneous patient populations; thus, it might not function optimally in all populations. For example, in a retrospective study of patients with solid tumors who seemed to be clinically stable, the MASCC risk index had a low sensitivity to detect complications (36 percent)31. The low sensitivity was likely to be attributed to the fact that patients were all outpatients, and the rates of hypotension, dehydration and invasive fungal infections were low; hence, only three criteria were present to distinguish prognosis.

The serious medical complications are provided by the MASCC risk index as follows 26:

? Hypotension defined as systolic blood pressure <90 mmHg or the need for vasopressor support to maintain blood pressure

? Respiratory failure defined as arterial oxygen pressure <60 mmHg on room air or the need for mechanical ventilation

? The admission to ICU

? Disseminated intravascular coagulation

? Presence of confusion, delirium, or altered mental status

? The development of congestive heart failure documented by chest imaging and requiring treatment

? Bleeding diathesis sufficient to require a blood transfusion

? Electrocardiogram changes or arrhythmias requiring treatment

? Renal failure sufficient to require an investigation and / or treatment with IV fluids, dialysis, or other intervention

? Other complications judged serious and clinically significant by the health care team

All patients who were treated with systemic antineoplastic therapy six weeks prior to a systemic inflammatory response syndrome (SIRS) are assumed to have neutropenic sepsis syndrome until proven otherwise. SIRS is defined by the presence of two or more of the following conditions: temperature >38¿½C or <36¿½C, heart rate> 90/minute, respiratory frequency > 20/minute, PaCO2 <32 mmHg32.

Patients presenting with altered mental status, hypotension, hypoxia, oliguria or any other sign of new organ impairment must be managed emergently for severe sepsis.

RISK OF TREATMENT FAILURE

The risk of failure to respond to initial empirical antibacterial therapy is a composite outcome to be considered clinicians. Treatment failure is proposed if one or more of the following events occur within 30 days after the start of treatment 33,34:

? Persistence, progression or recurrence of signs of infection

? Modification of the initial empirical antibacterial treatment

? Readmission to the hospital for outpatients

? Death

Patients with documented clinical or microbiological infections are more likely to be at risk for treatment failure, clinical or microbiological than for unexplained neutropenic fever (39 against 18 percent33.

High-risk patients are more likely to be at risk for treatment failure than those with low risk. For example, patients with hematologic malignancies have a higher percentage of treatment failure than those with solid tumors (44 against 18 percent) 33.

Observations have shown that among all febrile neutropenic patients at low risk of medical complications, adult patients at higher risk for treatment failure than children with 16% against 5% respectively34.

PREVENTION

In order to prevent neutropenic fever and infectious complications in patients at increased risk, the administration of an antimicrobial drug should be used as a prophylaxis.

Antibacterial prophylaxis

Pseudomonas aeruginosa and other gram-negative bacilli is the target of the antibacterial prophylaxis, because these pathogens are virulent and may cause life-threatening infections.

INDICATIONS

The beneficial effect on clinical outcomes has been sought from the administration of prophylactic antibacterial agents. The fluoroquinolones, levofloxacin (500 mg orally once daily) and ciprofloxacin (500 mg orally twice daily) have been the most studied antibacterial agents. Levofloxacin in particular is preferred in patients at increased risk for oral mucositis-related Streptococcus viridans infection 2. Results have been mixed with respect to effectiveness and have incited concern about toxicities and antibacterial resistance35¿½37. A systematic monitoring of the prevalence of fluoroquinolone resistance among gram-negative bacilli should be done, at the intitutions that use fluoroquinolone prophylaxis.

Based upon the available data, high-risk neutropenic patients defined by those who are expected to have an absolute neutrophil count <500 cells/microL for more than 7 days and who do not have a contraindication to receiving a fluoroquinolone, are recommended to receive fluoriquinolone prophylaxis. While, intermediate-risk patients are sometimes given an antibacterial prophylaxis, a decision made on a case-by-case basis.

Fluoroquinolone should be used with caution in patients at risk of a prolonged QT interval particularly in those who may require other QT prolonging agents, such as voriconazole.

In addition, the potential to promote resistance among gram-negative and gram-positive should be considered when deciding whether to give a fluoroquinolone prophylaxis or not37. Concerns about the possibility of increasing the risk of Clostridium difficile infection has also been present, though this has not been proven in neutropenic patients receiving fluoroquinolone prophylaxis37. The use of prophylactic agents in institutions and geographic areas where the levels of resistance to fluoroquinolones are high is less likely to be efficient36,38.The use of antibacterial prophylaxis varies from one center to another with some centers avoiding such practices.

For most patients with chemotherapy-induced neutropenia expected to be of short duration particularly patients with solid tumors, the use of antibacterial prophylaxis is not recommended.

TIMING

The ideal timing for the initiation and cessation antibacterial prophylaxis has not been sufficiently studied2. Many clinicians begin anti-bacterial prophylaxis, the first day of chemotherapy or the day after the administration of the last dose of chemotherapy cycle. Antibacterial prophylaxis is usually withheld when neutropenia resolves, or when empirical antibacterial regimen is initiated for patients who become febrile during neutropenia.

Antifungal prophylaxis

Among cancer patients and HCT recipients, a high rate of life-threatening invasive fungal infections such as candidemia has been observed since the late 1980s, which incited interest in antifungal prophylaxis for patients receiving chemotherapy.

Antiviral prophylaxis

INFLUENZA

Annual immunization with an inactivated influenza vaccine is recommended for all cancer patients undergoing treatment2. The influenza vaccine is generally administered >2 weeks before the initiation of chemotherapy or, when circumstances dictate, between chemotherapy cycles and at least seven days after the last cycle. However, the best timing for such immunization has not been established2. All family members and other close contacts should get annual immunization too.

HSV and VZV

Reactivation of herpes simplex virus (HSV-1 and HSV-2) and varicella-zoster virus (VZV) occur commonly in HCT recipients who are not receiving prophylaxis and are important causes of morbidity. However, reactivation of both HSV and VZV infections can be effectively prevented with antiviral prophylaxis.

Antiviral prophylaxis with acyclovir (400 mg orally three to four times daily or 800 mg orally twice daily) or valacyclovir (500 mg orally once or twice daily) is recommended in all patients who are seropositive for HSV and who are undergoing allogeneic HCT or induction chemotherapy for acute leukemia39. Antiviral prophylaxis with acyclovir or valacyclovir is also recommended in all HCT recipients who are seropositive for VZV. Based upon randomized trials, benefits of antiviral prophylaxis in these populations have been demonstrated; thus, recommended41.

CMV

CMV prophylaxis is indicated for HCT recipients because they are at are at significant risk for reactivation. In contrast, prophylaxis is not indicated in patients with chemotherapy-induced neutropenia, because it does not occur commonly.

HEPATITIS B

Antiviral prophylaxis should be considered for the following categories of patients and should be sustained for at least six months after the completion of chemotherapy40 :

? Patients receiving chemotherapy who have a previous history of hepatitis B virus infection, due to the risk of reactivation and hepatic failure.

? Patients with elevated circulating hepatitis B DNA or detectable levels of circulating hepatitis B surface antigen (HBsAg)

? Patients with a previous history of infection with detectable levels of antibody to HBsAg or to hepatitis B core antigen.

This has been demonstrated to be able to reduce the risk of reactivation from 24 to 53 percent to 0 to 5 percent.

Colony stimulating factors

Granulocyte colony stimulating factors (CSFs) have been widely evaluated for prophylactic use following the administration of intensive cytotoxic chemotherapy when neutropenia is expected (primary prophylaxis). CSFs have been also evaluated for their prophylactic use during retreatment after a previous cycle of chemotherapy that caused neutropenic fever (secondary prophylaxis), and have been shown to minimize the extent and duration of severe chemotherapy-induced neutropenia in afebrile patients (afebrile neutropenia). Their use is not recommended in febrile chemotherapy-induced neutropenia2. However, prophylactic use of granulocyte CSFs has not been shown to have an effect on survival in most clinical situations.

PRIMARY PROPHYLAXIS

Primary prophylaxis denotes the use of granulocyte CSFs during the first cycle of myelosuppressive chemotherapy in order to prevent neutropenic complications. The goal of primary prophylaxis is to decrease the incidence of neutropenic fever and the need for hospitalization, to maintain dose-dense or dose-intense chemotherapy strategies that have survival benefits.

Updated 2010 guidelines from the European Organization for Research and Treatment of Cancer (EORTC), the Infectious Diseases Society of America (IDSA), consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), and The 2006 guidelines from the American Society of Clinical Oncology (ASCO), all recommend primary prophylaxis when the expected incidence of neutropenic fever is over 20 percent, to reduce the need for hospitalization for antibiotic therapy2,22,41. These recommendations are based upon randomized trials that have shown that primary prophylaxis was cost effective when the risk of neutropenic fever with a specific regimen was over 20 percent42,43 .

In contrast, guidelines recommend against the routine use of granulocyte CSFs for primary prophylaxis in adult patients receiving chemotherapy regimens with an anticipated low probability (<10 percent) of neutropenic fever2,22,41 .

However, when the anticipated risk of neutropenic fever is between 10 and 20 percent, the decision of primary prophylaxis should be individualized and may be appropriate in a number of clinical settings in which patients are at risk or increased complications22,41 :

¿½ Age >65 years

¿½ Preexisting neutropenia

¿½ More advanced cancer

¿½ Poor performance and/or nutritional status

¿½ Renal or hepatic impairment

¿½ In the case of epithelial ovarian cancer

¿½ Extensive prechemotherapy surgery, particularly if it included a bowel resection.

In patients receiving concomitant chemoradiotherapy for either head and neck cancer or lung cancer, the use of granulocyte CSFs has been associated with adverse outcomes, therefore, it better be avoided.

Despite the lack of comparative data from randomized controlled trials, that could recommend one CSF over the other for prophylaxis of infection during chemotherapy-induced neutropenia, in practice, most institutions use G-CSF.

SECONDARY PROPHYLAXIS

Secondary prophylaxis denotes to the use of a granulocyte CSF in subsequent chemotherapy cycles after a prior cycle has caused neutropenic fever. Secondary prophylaxis with CSFs reduces the risk of reccurence of neutropenic fever by approximately one-half 44.

ASCO and EORTC guidelines recommend that secondary prophylaxis with granulocyte CSFs be limited to patients for whom primary prophylaxis was not given and who experience a neutropenic complication from a prior cycle of chemotherapy if neutropenic fever would prevent the administration of full dose chemotherapy and if reduced dose intensity might affect treatment outcome22,41 .

TIMING

G-CSF and GM-CSF therapy is usually initiated 24 to 72 hours after cessation of chemotherapy and is frequently continued until the absolute neutrophil count reaches 5000 to 10,000/microL. A reasonable alternative is continuation until clinically adequate neutrophil recovery.

MANAGEMENT

Initial Assessment

Since, fever might be the first and only sign of infection in a neutropenic patient, its occurrence should be considered a medical emergency. Therefore, empiric broad-spectrum antibacterial therapy should be started immediately after blood cultures have been obtained and before any other investigations have been completed. The Infectious Diseases Working Party of the German Society of Hematology and Oncology and the Northern Ireland Cancer Network has recommended this.

It has been recommended that empiric broad-spectrum antibacterial therapy should be administered within 60 minutes of presentation for all patients suffering from neutropenic fever at presentation. (algorithm 1)

Diagnostic Approach

At presentation, a detailed history and physical examination should be done, as well as a complete laboratory, microbiologic and imaging work-up for all febrile neutropenic patients.

The table below summarizes the diagnostic approach to patients with febrile neutropenia.

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