Febrile neutropenia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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

Table 1. Common Bacterial Pathogens in Neutropenic Patients
Gram-Positive Pathogens
Coagulase-negative staphylococci Staphylococcus aureus, including methicillin-resistant strains Enterococcus species, including vancomycin-resistant strains Viridans group streptococci Streptococcus pneumoniae Streptococcus pyogenes
Gram-Negative Pathogens
Escherichia coli Klebsiella species Enterobacter species Pseudomonas aeruginosa Citrobacter species Acinetobacter species Stenotrophomonas maltophilia
Table 2. Medical Complications Considered Serious
Hypotension: systolic blood pressure less than 90 mmHg or need for pressor support to maintain blood pressure Respiratory failure: arterial oxygen pressure less than 60 mmHg while breathing room air or need for mechanical ventilation Intensive care unit admission Disseminated intravascular coagulation Confusion or altered mental state Congestive cardiac failure seen on chest x-ray and requiring treatment Bleeding severe enough to require transfusion Arrhythmia or ECG changes requiring treatment Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention Other complications judged serious and clinically significant by the investigator†
† All reviewed by one investigator. Viral or fungal, microbiologically documented primary infection during the febrile episode, without any described complication and resolving under therapy, was considered a part of the infectious process and was not considered a serious complication.
Table 3. MASCC Risk Index Score
Characteristic Burden of febrile neutropenia with no or mild symptomsa No hypotension (systolic blood pressure >90 mmHg) No chronic obstructive pulmonary diseaseb Solid tumor or hematologic malignancy w/o prior fungal infectionc No dehydration requiring parenteral fluids Burden of febrile neutropenia with moderate symptomsa Outpatient status Age <60 years	Weight 5 5 4 4 3 3 3 2
The maximum value of the score is 26. a Burden of febrile neutropenia refers to the general clinical status of the patient as influenced by the febrile neutropenic episode. It should be evaluated on the following scale: no or mild symptoms (score of 5); moderate symptoms (score of 3); and severe symptoms or moribund (score of 0). Scores of 3 and 5 are not cumulative. b Chronic obstructive pulmonary disease means active chronic bronchitis, emphysema, decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators requiring treatment at the presentation of the febrile neutropenic episode. c Previous fungal infection means demonstrated fungal infection or empirically treated suspected fungal infection.
Table 4. Antimicrobial Prophylaxis for Cancer-Related Infections
Low Risk
Bacterial – None Fungal – None Viral – None except positive HSV serology
Intermediate Risk
Bacterial – Consider fluoroquinolone prophylaxis Fungal – Consider antifungals during neutropenia and for anticipated mucositis Viral – During neutropenia and at least 30 days after HSCT
High Risk
Bacterial – Consider fluoroquinolone prophylaxis Fungal – Consider antifungals during neutropenia and for anticipated mucositis Viral – During neutropenia and at least 30 days after HSCT; also consider pre-emptive therapy against CMV or HBV
Table 5. Antifungal Prophylaxis in Patients with Cancer
Disease/Therapy ALL AML MDS Autologous HSCT with mucositis Allogenic HSCT GVHD	Antifungal prophylaxis Fluconazole Posaconazole Posaconazole Fluconazole or micafungin Fluconazole or micafungin Posaconazole

Febrile neutropenia is a condition characterized by a decrease in neutrophils (neutropenia) associated with the development of fever, the latter indicating the presence of an infection.^[1] The majority of patients have no identifiable site of infection and no positive culture results. Nonetheless, urgent treatment with empirical antibiotics is recommended in light of the possibility of rapid progression.^[2]

In 1966, Bodey et al. first described the quantitative association between leukocyte counts and the incidence of infection in a study of acute leukemia which demonstrated that the risk and the type of infection are related to the severity and duration of granulocytopenia.^[3] Infection risk begins to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm³ and rises markedly when the ANC drops to less than 500 cells/mm³. When the causative pathogen is identifiable, bacterial or viral etiology predominates within the first seven days of neutropenic fever, while infection with antibiotic-resistant bacteria or invasive fungi occurs more often in the setting of protracted neutropenia.^[4]

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

Bloodstream infections caused by endogenous flora and reactivation of latent infections account for a majority of initial febrile episode in neutropenic patients with cancer.

Approximately 10% to 50% of patients with solid tumors and more than 80% of those with hematologic malignancies will develop fever during courses of cytotoxic chemotherapy. However, an infectious etiology can be established in a minority of patients, and clinically defined infections occur in 20% to 30% of febrile episodes.^[5]

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

Template:Seealso

The National Comprehensive Cancer Network (NCCN) devised a set of overall infection risk categories (low, intermediate, and high) in patients with cancer based on factors such as the underlying malignancy, disease status (eg, active disease, disease in remission), duration of neutropenia, prior exposure to chemotherapy, and intensity of immunosuppressive therapies.^[6]

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

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

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

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

According to the IDSA Practice Guideline, neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm³ or an ANC that is expected to decrease to <500 cells/mm³ during the next 48 hours, and fever is defined as a single oral temperature measurement of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a 1-hour period.

Either the clinical judgment criteria or the MASCC assessment tool can be used to stratify risk for patients presenting with fever and neutropenia. Initial assessment should then inform decisions about the type of regimen and appropriate venue for delivery of empirical antibiotics, as well as the timing of hospital discharge. High-risk patients should initially receive IV empirical antibiotic therapy in the hospital, whereas low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.^[7]

Pertinent history should include new site-specific symptoms, prior use of antimicrobial agents, potential infection exposures, previous documented infections or pathogen colonization, catheter or device placement, and co-existence of noninfectious causes of fever, such as blood product administration. Underlying co-morbidities, such as diabetes, chronic obstructive lung disease, and/or recent procedures, should also be noted.

In neutropenic patients, manifestations secondary to inflammation are attenuated and fever is often the only clue indicative of an underlying infection.

The physical examination should focus on potential sites of infection.^[8] Induration and erythema of the skin may be minimal. Pustule formation are uncommon in the absence of neutrophils. Examination of the oropharynx may reveal ulcers or plaques suggestive of herpes or candidiasis. Mucositis owing to cytotoxic chemotherapy may be indistinguishable from herpetic gingivostomatitis. Auscultation of the lungs may reveal minimal adventitial sounds. Abdominal pain in neutropenic patients may herald an intraabdominal catastrophe secondary to neutropenic enterocolitis or tumor necrosis. Examination of catheter sites may disclose erythema, tenderness, or discharge.

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

Chest radiography should be reserved for patients with symptoms of respiratory tract infection.^[9]

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

Routine test of inflammation markers, such as C-reactive protein, IL-6, IL-8, or procalcitonin, to guide clinical decisions is not recommended.^[10]

Generally, patients with febrile neutropenia are treated with empirical antibiotics until the neutrophil count has recovered (absolute neutrophil counts greater than 500/mm³) and the fever has abated; if the neutrophil counts fail to restore, treatment may need to continue for two weeks or more. In cases of recurrent or persistent fever, an antifungal agent should be added.

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

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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

Bodey et al. first described the quantitative association between leukocyte counts and the incidence of infection in a study of acute leukemia in 1986.

In 1966, Bodey et al. first described the quantitative association between leukocyte counts and the incidence of infection in a study of acute leukemia which demonstrated that the risk and the type of infection are related to the severity and duration of granulocytopenia.^[1] Infection risk begins to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm³ and rises markedly when the ANC drops to less than 500 cells/mm³. When the causative pathogen is identifiable, bacterial or viral etiology predominates within the first seven days of neutropenic fever, while infection with antibiotic-resistant bacteria or invasive fungi occurs more often in the setting of protracted neutropenia.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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

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

A number of factors pose an increased risk for infections in cancer patients:

• Absolute or functional leukopenia

Leukocytes, particularly neutrophils, constitute one of the front-line defense mechanisms against invading microorganisms. Chemotherapy is associated with both qualitative and quantitative deficits in circulating neutrophils by lowering neutrophil counts and impairing chemotaxis and phagocytosis, respectively.

• Altered microbiota

Microbiota that inhabit the skin, respiratory tract, and digestive tract may be altered by cancer and its treatment or the use of antibiotics.^[1]

• Breaches of natural barriers

Mucositis may occur as a direct adverse effect of chemotherapy or radiotherapy and disrupt the barrier function of the endothelial lining. Indwelling catheters and implanted devices allow access of skin commensals into blood or subcutaneous tissues or serve as a biofilm which bacteria can colonize. Solid tumors that overgrow their blood supply may undergo necrosis and form a nidus for infection.

• Immune defects associated with specific primary malignancies

Patients with leukemias, non-Hodgkin’s lymphoma, or myelodysplastic syndrome may be leukopenic due to malignant infiltration or marrow dysfunction. Absolute or functional hypogammaglobulinemia predisposes patients with chronic lymphocytic leukemia or multiple myeloma to recurrent sinopulmonary infections and septicemia caused by encapsulated pathogens such as Streptococcus pneumoniae and Haemophilus influenza.^[2][3] An increased risk of infection has also been observed in patients with Hodgkin’s lymphoma as a result of defective cell-mediated immunity.

• Hyposplenism

Production of opsonizing antibodies takes place in the spleen. Hyposplenism, either as a complication of graft-versus-host disease or irradiation, may contribute to overwhelming infection with encapsulated bacteria.

• Lymphotoxicity

High-dose corticosteroids affect the distribution and function of lymphocytes as well as other immunocytes. Fludarabine, an adenosine analogue, depletes CD4+ lymphocytes and increases the risk of listeriosis, mycobacterial infections, and opportunistic infections.^[4] Therapy with alemtuzumab, a humanized monoclonal antibody targeting CD52 on lymphocytes, heightened the risk for a wide variety of infections.^[5][6][7] In addition, the use of anti-CD20 monoclonal antibodies such as rituximab and ofatumumab has been associated with an escalated risk for hepatitis B virus reactivation.^[8]

Template:Seealso Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogheneochuko Ajari, MB.BS, MS [2]

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

Bloodstream infections caused by endogenous flora and reactivation of latent infections account for a majority of initial febrile episode in neutropenic patients with cancer. Bacterial isolates commonly cause bacteremia in the setting of neutropenia followed by fungi and viruses.^[1]. Certain endogenous microorganisms may be reactivated and exit latency during immunosuppression. These include herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, hepatitis B and C viruses, and Mycobacterium tuberculosis. Exogenous pathogens carried by contaminated blood products, medical equipment and devices, water sources, and health care workers represent less common sources of infection. These include Clostridium difficile, respiratory syncytial virus, vancomycin-resistant enterococci, and other multidrug resistant bacteria.^[2]. Fungal infections often take place in the setting of prolonged or profound neutropenia after administration of empirical therapy. Candidiasis may range in severity from mucosal or cutaneous infection to septicemia, endocarditis, or disseminated infection. Aspergillus, on the contrary, typically causes life-threatening infection of the sinuses and lungs, particularly after protracted neutropenia.^[3]

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Febrile neutropenia is a life threatening condition and must be treated as such irrespective of the underlying cause.

• Acinetobacter spp
• Citrobacter spp
• Coagulase-negative staphylococci
• Enterobacter spp
• Enterococcus spp, including vancomycin-resistant strains
• Escherichia coli
• Klebsiella spp
• Pseudomonas aeruginosa
• Staphylococcus aureus, including methicillin-resistant strains
• Stenotrophomonas maltophilia
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Viridans group streptococci

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	Cellulitis
Drug Side Effect	Chemotherapy
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	Acinetobacter, anaerobes, aspergillus, babesia, bacillus, candida, capnocytophaga canimorsus, cellulitis, citrobacter, clostridium difficile, coagulase-negative staphylococci, coccidioides spp, corynebacterium jeikeium, cryptococcus, cytomegalovirus, enterobacter, enterococcus, enteroviruses, Epstein-Barr virus, escherichia coli, hemophilus influenzae, herpes simplex virus, histoplasma capsulatum, human herpesvirus 6, influenza virus, klebsiella , legionella,listeria monocytogenes, moraxella, mucorales, mycobacteria, neisseria meningitidis, nocardia, parainfluenza virus, plasmodium,pneumocystis jirovecii, pneumonia, proteus, pseudomonas aeruginosa, respiratory syncytial virus, serratia, staphylococcus aureus, stenotrophomonas maltophilia, stomatococcus, streptococcus pneumoniae, streptococcus pyogenes, strongyloides stercoralis, toxoplasma, varicella zoster virus, viridans group streptococci
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Malignancy
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Pneumonia
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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

Approximately 10% to 50% of patients with solid tumors and more than 80% of those with hematologic malignancies will develop fever during courses of cytotoxic chemotherapy. However, an infectious etiology can be established in a minority of patients, and clinically defined infections occur in 20% to 30% of febrile episodes.^[1]

Approximately 10% to 50% of patients with solid tumors and more than 80% of those with hematologic malignancies will develop fever during courses of cytotoxic chemotherapy. However, an infectious etiology can be established in a minority of patients, and clinically defined infections occur in 20% to 30% of febrile episodes.^[2]

Over the past few decades, there has been a shift in the spectrum of bacterial isolates from patients with febrile neutropenia. Gram-negative organisms prevailed in the era when cytotoxic chemotherapy was initially introduced, whereas Gram-positive skin flora including coagulase-negative staphylococci evolved as the most common isolates after widespread use of indwelling catheters and prophylactic antibiotics. In addition, there has been a drift in susceptibility patterns, with resistance seen in the general population of hospitalized patients now emerging in febrile neutropenic patients.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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

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

Template:Seealso

The National Comprehensive Cancer Network (NCCN) devised a set of overall infection risk categories (low, intermediate, and high) in patients with cancer based on factors such as the underlying malignancy, disease status (eg, active disease, disease in remission), duration of neutropenia, prior exposure to chemotherapy, and intensity of immunosuppressive therapies.^[1]

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

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

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

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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

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

Table 2. Medical Complications Considered Serious
Hypotension: systolic blood pressure less than 90 mmHg or need for pressor support to maintain blood pressure Respiratory failure: arterial oxygen pressure less than 60 mmHg while breathing room air or need for mechanical ventilation Intensive care unit admission Disseminated intravascular coagulation Confusion or altered mental state Congestive cardiac failure seen on chest x-ray and requiring treatment Bleeding severe enough to require transfusion Arrhythmia or ECG changes requiring treatment Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention Other complications judged serious and clinically significant by the investigator†
† All reviewed by one investigator. Viral or fungal, microbiologically documented primary infection during the febrile episode, without any described complication and resolving under therapy, was considered a part of the infectious process and was not considered a serious complication.

High-risk patients as assessed by clinical judgment criteria or MASCC Risk Index are more likely to develop serious complications of febrile neutropenia including intensive care unit admission, confusion, cardiac complications, respiratory failure, renal failure, hypotension, bleeding, and death (Table 2).^[1]