Febrile neutropenia is the development of

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

, often with other signs of

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

, in a patient with

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

, an abnormally low number of

neutrophil granulocyte Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

s (a type of

white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

) in the blood. It is an oncologic emergency, and is the most common serious complication in patients with hematopoietic cancers or receiving chemotherapy for cancer. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well. In 50% of cases, an infection is detectable;

bacteremia Bloodstream infections (BSIs) are infections of blood caused by blood-borne pathogens. The detection of microbes in the blood (most commonly accomplished by blood cultures) is always abnormal. A bloodstream infection is different from sepsis, wh ...

(bacteria in the bloodstream) is present in approximately 20% of all patients with this condition.

Definition

Febrile neutropenia or neutropenic fever is a defined as a single oral temperature value of ≥ 38.3 C (101 F) or a temperature ≥ 38 C (100.4 F) for ≥ 1 hour, with an absolute neutrophil count (ANC) < 1500 cell/microliter. In case of severe neutropenia, the ANC is < 500 cell/microliter. In profoundly severe neutropenia, the ANC is < 100 cells/microliter.

Pathophysiology

Febrile neutropenia can develop in any form of neutropenia, but is most generally recognized as a complication of

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

when it is

myelosuppressive Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting ( ...

(suppresses the

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

from producing blood cells). Febrile neutropenia is the most common and serious complication in patients with hematopoietic cancers or receiving chemotherapy for cancer. The condition occurs when a neutropenic patient gets infected by a pathogen. Approximately 50% of patients with febrile neutropenia develop an infection, of which 20% with profound neutropenia will develop bacteremia.

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain ...

are now the most common pathogens causing febrile neutropenia, with many of these infections resulting from long-term

central venous catheter A central venous catheter (CVC), also known as a central line (c-line), central venous line, or central venous access catheter, is a catheter placed into a large vein. It is a form of venous access. Placement of larger catheters in more centr ...

Diagnosis

MASCC and CISNE risk indexes

The Multinational Association for Supportive Care in Cancer (MASCC) risk index can be used to identify low-risk patients (score ≥21 points) for serious complications of febrile neutropenia (including death,

intensive care unit An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensive care medicine. An inten ...

admission, confusion, cardiac complications,

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

, low blood pressure,

bleeding Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethr ...

, and other serious medical complications). The score was developed to select patients for therapeutic strategies that could potentially be more convenient or cost-effective. A prospective trial demonstrated that a modified MASCC score can identify patients with febrile neutropenia at low risk of complications, as well. In contrast, the Clinical Index of Stable Febrile Neutropenia (CISNE) score is specific of patients with solid tumors and seemingly stable episodes. CISNE is able to discriminate groups of patients who are at low, intermediate, and high risk of complications in this population. With the CISNE, the complication rate was determined to be 1.1% for low-risk patients, 6.2% for intermediate-risk patients, and 36.0% for high-risk patients. The prime purpose of this model was to avoid complications from an early hospital release. On the contrary, CISNE should not be used so much to select low-risk patients for outpatient treatment.

Treatment

Generally, patients with febrile neutropenia are treated with empirical

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

s until the neutrophil count has recovered (absolute neutrophil counts greater than 500/mm³) and the fever has abated; if the neutrophil count does not improve, treatment may need to continue for two weeks or occasionally more. In cases of recurrent or persistent fever, an antifungal agent should be added. Guidelines issued in 2002 by the

Infectious Diseases Society of America The Infectious Diseases Society of America (IDSA) is a medical association representing physicians, scientists, and other health care professionals who specialize in infectious diseases. It was founded in 1963 and is based in Arlington, Virginia. ...

recommend the use of particular combinations of antibiotics in specific settings; mild low-risk cases may be treated with a combination of oral amoxicillin-clavulanic acid and

ciprofloxacin Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin ...

, while more severe cases require

cephalosporin The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus '' Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibio ...

s with activity against ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common Bacterial capsule, encapsulated, Gram-negative bacteria, Gram-negative, Aerobic organism, aerobic–facultative anaerobe, facultatively anaerobic, Bacillus (shape), rod-shaped bacteria, bacterium that can c ...

'' (e.g.

cefepime Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 ...

), or

carbapenem Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Si ...

s (

imipenem Imipenem (trade name Primaxin among others) is a synthetic beta-lactam, β-lactam antibiotic belonging to the carbapenems chemical class. developed by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Car ...

meropenem Meropenem, sold under the brand name Merrem among others, is an intravenous carbapenem antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax. C ...

). A subsequent

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

published in 2006 found cefepime to be associated with more negative outcomes, and carbapenems (while causing a higher rate of

pseudomembranous colitis Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases. In a medical context, the label ''colitis'' (without qualificati ...

) were the most straightforward in use. In 2010, updated guidelines were issued by the Infectious Diseases Society of America, recommending use of cefepime, carbapenems (meropenem and imipenem/cilastatin), or piperacillin/tazobactam for high-risk patients and amoxicillin-clavulanic acid and ciprofloxacin for low-risk patients. Patients who do not strictly fulfill the criteria of low-risk patients should be admitted to the hospital and treated as high-risk patients. Research to compare antibiotic treatments currently recommended in consensus guidelines identified 44 studies comparing different antibiotics. Significantly higher mortality was reported for cefepime compared to all other antibiotics combined.

Piperacillin/tazobactam Piperacillin/tazobactam, sold under the brand name Tazocin among others, is a combination medication containing the antibiotic piperacillin and the β-lactamase inhibitor tazobactam. The combination has activity against many Gram-positive and G ...

resulted in lower mortality than other antibiotics. Piperacillin/tazobactam might be the preferred antibiotic for the treatment of cancer patients with fever and neutropenia, while cefepime should not be used. Empiric treatment should be started within 60 minutes of being admitted. Periodic monitoring should be done to see if the empiric treatment is working, or if a more target therapy should be initiated. In people with cancer who have febrile neutropenia (excluding patients with acute leukaemia), oral treatment is an acceptable alternative to intravenous antibiotic treatment if they are hemodynamically stable, without organ failure, without pneumonia and with no infection of a central line or severe soft-tissue infection. Furthermore, outpatient treatment for low‐risk febrile neutropenia in people with cancer probably makes little or no difference to treatment failure and mortality compared with the standard hospital (inpatient) treatment and may reduce time that patients need to be treated in hospital.

References

External links

Febrile neutropenia
entry in the public domain NCI Dictionary of Cancer Terms {{DEFAULTSORT:Febrile Neutropenia Monocyte and granulocyte disorders Oncology Oncological emergencies