Febrile neutropenia

The most serious clinical complication in patients with cancer undergoing chemotherapy.

An oncologic emergency.

Patients with neutropenic fever usually have a temperature of 100.4°F or greater with an absolute neutrophil count of less than 500-1000 cells/ml.

Relationship of circulating neutrophil count and the risk of pyogenic infection.

Infectious Diseases Society of America defines fever as a single oral temperature of 101° or greater or a temperature of 100.4°F lasting more than one hour, and defines neutropenia as an absolute neutrophil count of less than 500 cells/ mm3.

More than 60,000 patients were hospitalized in 1999 for febrile neutropenia.

in the US the incidence of drug induced neutropenia is 2.4 to 15.4 cases per million each year and the incidence of febrile neutropenia is 7.8 cases per thousand patients with cancer.““

Approximately 1% of patients with cancer chemotherapy develop febrile neutropenia.

Most chemotherapy regimens are associated with 6-8 days of neutropenia.

Fever is often the only sign of infection in a patient with neutropenia, so fever and neutropenia must be treated as a medical emergency.

Febrile neutropenia can lead to hospitalization and treatment with antibiotics, as well as chemotherapy dose delays, dose reductions and or treatment discontinuation.

Absolute neutrophil count (ANC) is defined as number of segmented neutrophil and bands circulating in the blood and neutropenia defined as the ANC below a threshold usually 0.5-1.0 x 10th to the 9th /L.

Majority of febrile episodes observed with ANC below 0.5 x 10th to the 9th/L.

A relationship exists for absolute lymphocyte count of less than .75 x 10th to the 9th/ at day 5 of cytotoxic therapy and infection.

Patients at risk for serious bacterial infection.

Factors associated with febrile neutropenia include: older age, advanced disease, poor performance status, history of FN, infection, recent surgery or open wounds, prior chemotherapy, bone marrow involvement, and the presence of pulmonary, renal, hepatic, or cardiovascular comorbidities.

SN represents a significant burden, predisposing patients to serious and often in life-threatening infections that can result in hospitalization, antibiotic treatment, reduced intensity or delay 2critical chemotherapy treatment, and diminishing quality of life.

Patients with neutropenic fever should receive empiric broad-spectrum anabiotic therapy within 60 minutes of presentation.

More than 60,000 patients admitted annually for FN in the US.

Approximately 8 cases of FN occur per 1000 patients receiving chemotherapy (Caggiano V et al).

Bacterial infections predominate during the initial phases of neutropenic episode (Bodey GP).

FN associated with serious infections, and death, especially with neutropenia of greater than 10-14 days.

FN places a significant burden on patients with cancer, in terms of hospitalizations and mortality and in terms of healthcare costs.

Most patients with F.N or hospitalized with an average length of stay at six days for elderly patients, about eight days for children, and up to 10 days for adults.

Reviews suggest mortality rates for children with cancer hospitalized for FN are .4 to 3%, with rates of 2.6 to 7% in adults with solid tumors and 7.4% in adults with hematologic malignancies.

The most serious infections with febrile neutropenia occur with gram-negative bacteria, gram-positive bacterial infections, fungal infections, and viral infections, generating significant morbidity and possible mortality in immunocompromise neutropenic hosts.

In a retrospective study of chemotherapy patients over the age of 40 years with a total of 15,638 patients neutropenic related hospitalization occurred in 8.7% of non-Hodgkin’s lymphoma patients, 4.2% of breast cancer patients and 3.9% of lung cancer patients (Henk H et al ).

In the above study the highest risk of neutropenia related hospitalization was observed in the NHL patients, whose risk increased with advancing age, and it indicated that age is an important component in the determination of risk.

The association of age with the risk of neutropenic related hospitalization varies with the type of malignancy, as indicated by the above studies.

Risk stratification is used to determine the type of empirical therapy required.

The Multinational Association oF Supportive Care in Cancer score uses criteria such as age, symptom severity and comorbidities, all of which is given a weighted numerical value- score of > than 21 is high risk and less than 21 is low risk.

Risk stratification helps determine the route of antibiotics, duration of tretment and location of trreatment.

Outpatient treatment may be considered for low risk patients with favorable conditions such as hemodynamic stability, lack of comorbid conditions, good performance status, no renal or heptic dysfunction, and absence of organ dysfunction.

For low risk outpatients empirical tretment of oral fluoroquinolones with the addition of amoxicillin/clavulanate or clinidamycin are generally recommended.

Follow-up for outpatient managment include frequent evaluation for at least 3 days, with monitoring of blood counts, and daily phone communications about the patients status.

Death rate in hospitalized patients 6.8%, and up to 15.3% in patients with documented infections (Caggiano V et al, Kuderer NM et al).

Chemotherapy induced leukopenia associated with production of endogenous cytokines IL-6. And TNF, which can cause fever, even in the absence of infection,

Neutrophils are early responders to bacterial pathogens

Gram-negative bacilli were the most commonly identified pathogens in patients with neutropenic fever and hematologic malignancies up until the 1980s.

Pseudomonas species is associated one of the highest mortality rates from bacterial pathogens in patients with neutropenic fever.

Bacteremia occurs in approximately 20% of patients with febrile neutropenia with gram-positive organisms accounting for the majority of infections.

Recent evaluations show that the most common pathogens for neutropenic fever are gram-positive organisms accounting for 62-76% of bloodstream infections.

The increase in the number of gram-positive pathogens is related to the use of long-term indwelling central venous catheters, the use of it in empirical anabiotics used to cover gram-negative organisms and increase use of prophylactic anabiotics targeting gram-negative organisms.

The Multinational Association of Supportive Care of Cancer (MASCC) risk index score helps predict which patients presenting with febrile neutropenia are at low high-risk of developing complications.

The above tools contains eight factors that allow assessment: Patients with a score of 21 or greater are considered low risk, lower scores are considered high-risk need more intensive management.

Poor predictors of prognosis include: individuals older than 60 years of age, moderate symptoms with febrile neutropenia, hypotension, dehydration, and prior fungal infection.

Standard intravenous therapy previously consisted of empirical treatment with a synergistic combination of beta lactam antibiotic plus an aminoglycoside.

Initiation of anti–pseudomonal beta-lactam with mono therapy with meropenem, cefipime, or piperacillin-tazobactam to cover gram-positive, gram-negative infections: vancomycin should be added if a catheter associated infection, skin or soft tissue infection or hypotension are present.

Most common gram-positive organisms identified as neutropenic fever pathogens are staphylococcal aureus, staphylococcal epidermidis, streptococci species and viridans group streptococci.

Gram-positive infections predominate among neutropenic patients and are derived from skin colonization.

Infections with gram-negative bacilli such as Escherichia coli, Pseudomonas, Klebsiella, and yeasts are less frequent but more lethal.

E. coli, Pseudomonas, and klebsiella have been cultivated from the surfaces of foods, usually fruits, cold meats, lettuce, and other vegetables.

Gram-negative organisms and yeast infections into the bloodstream via the gastrointestinal tract.

Disruption of the mucosa area as a consequence of chemotherapy, induces mucositis, and has a significant contributing factor to neutropenic infections.

No studies have found a causal role for food derived enteric bacteria subsequent serious infections during neutropenia.

Food is a possible vehicle for pathogenic bacteria in the immunosuppressed individuals and include foodborne pathogens Campylobacter jejuni, Salmonella, Escherichia coli, and Clostridium perfringens.

Safe food handling methods are recommended for neutropenic patients rather than specific avoidance of fruits and vegetables.

No standard definition of a neutropenic diet exixts, but commonly prohibited foods include fresh raw fruits, and vegetables, but many centers ovoid fresh squeezed juices, dried fruits, yogurt, aged cheeses, deli meats, nuts, undercooked meats, undercooked seafood and undercooked eggs.

In a randomized study of 153 patients undergoing induction chemotherapy for acute myelogenous leukemia to either a diet containing raw fresh fruits and vegetables or one that exclude those items: Among patients receiving cooked-diet major infections occurred in 29%, compared with 35% and one Thiokol, it trained toward fewer fevers of unknown origin in the cooked I will, but the probability of death not different between the groups (Gardner a et al).

In the above study, the overall incidence of bacteremia was higher in the raw-diet group, but there was no difference in isolation of organisms that normally reside in the GI tract.

In the above study the incidence of pneumonia was higher than in the cooked-diet group, 15% versus 5%.

In a retrospective study of 726 consecutive the medical expense transplant recipients randomized to a neutropenic diet or general diet and see if we can there was no significant difference in microbiologic reconfirmed infections between groups (Trifilio S et al).

Neutropenic diet has variability and have no clear significant benefit to patients.

Techniques to provide protective environments including lamina flow rooms, shaving of genitourinary or, viral cleansing of toenails and fingernails, bathing in iso-propryl alcohol or hexachlorophene, sterilization of close and linens, sterilization of food, cleansing of the GI tract, sterilization of the GI tract with antibiotics have no proven benefit.

Many gram-positive organism associated with neutropenic fever such as coagulase negative staphylococci, Corynebacterium spp., MRSA and vancomycin-resistant enterococci, and viridans are resistant to antimicrobacterial agents frequently used for prophylaxis and empiric treatment.

While vancomycin has been used empirically in neutropenic feverit has not been shown to improve responses in regimens that do not contain vancomycin ((Rubin M, Cometta A, Feld R).

Direct relationship exists between granulocytopenia and infectious complications.

Considering the patient’s diagnosis, risk factors, chemotherapy regimen and treatment intent, the risk of developing febrile neutropenia can be classified as low, medium or high.

More than 50% of cases will not be accompanied by clinical or microbiological evidence of infection.

Patients with neutropenia may not have an inflammatory response visible on chest x-ray, and for those who have a normal chest x-ray findings they should undergo CT chest examination when they have persistent fever.

More than 50% of neutropenic patients with a normal chest x-ray have evidence of pneumonia on CT scan.

CT scans of the abdomen and pelvis can also identified etiologies of persistent fever in neutropenic patients such as a abscess, neutropenic colitis, cholecystitis, or appendicitis.

Complicates chemotherapy for solid tumors in about 20% of patients and in approximately 80% of patients treated for hematological malignancies.

Mortality is about 10%, but much higher in certain risk groups, and is related to the presence of sepsis, and clinical evidence of infection, the level of control of the malignancy and other comorbidities.

Mortality rates in patients with cancer patients .range fro 5-20%

75% of patients have a 5-10% risk of severe complications.

The use of nonabsorbable prophylactic antibiotics to eradicate normal enteric flora and aerobic gram-negative bacteria and thereby reduce gut bacterial burden available for translocation had limited success.

In a healthy person bacteria passes through the GI tract without adhering to the mucosal surface: It will be destroyed by stomach acid, or competed out of existence by normal endogenous flora- in neutropenic patient’s stomach reduced acidity may impair bacterial killing, GI mucositis promotes translocation of bacteria and antibiotic suppression of endogenous flora prevents bacterial competition and allows overgrowth of potentially pathogenic bacteria.

Daptomycon (Cubicin) in febrile neutropenia with documented gram-positive infections, (CORE) Cubicin Outcome Registry and Experience, and most patients having received prior antibiotics, associated with an overall success rate of 90% (Rolston K).

The timing of initial antibiotic therapy is to initiate antibiotics within 1-2 hours of admission.

Orally administered antibiotics such as amoxicillin/clavulanate plus ciprofloxacin are as effective as intravenous therapy if patients are at low risk of complications, with an overall response rate of greater than 80%.

Antifungal therapy should be heading in patients with persistent HP-UX fever after more than 47 days of appropriate antibiotics if the duration of neutropenic is expected to be prolonged more than seven days.

Guidelines recommend taking a minimum of 2 sets of blood cultures from 1 peripheral and 1 central site.

Blood cultures should be obtained from central venous catheters and from the peripheral blood in all patients with febrile neutropenia, ideally before the administration of antibiotic management.

Routine in discriminate chest x-ray at the time of first neutropenic fever in asymptomatic patient undergone stem cell transplant is unlikely to reveal an infectious process or change clinical practice (Yolin-Raley DS et al).

The routine use of chest x-ray as an initial evaluation of asymptomatic patients with febrile neutropenia is controversial as the yield of conventional x-rays is low in the early stages of pneumonia because of diminished inflammatory response.

Persistent neutropenic fever syndrome occurs when patients remain continuously febrile and neutropenic after initiation of broad-spectrum antibiotic therapy.

Persistent neutropenic fever patients should be hospitalized and empirical antifungal therapy initiated in patients who show no response to broad-spectrum antibiotics after 4 – 7 days, and who are expected to remain neutral for more than 7 days.

Empirical anti-fungal agents should provide coverage against fluconazole resistant candida infections and molds such as aspergillosis, the most common invasive mold.

Antibacterial and anti-fungal prophylaxis is considered as a preventative measure inpatients at high risk for febrile neutropenia: recommendations are using antibacterial and anti-fungal prophylaxis in patients whose neutrophil counts are expected to be below 100 cells per microliter for more than seven days.

Prophylactic antibiotic use in low-risk patients who are expected to remain neutropenic for fewer than seven days is not supported by guidelines.

Granulocyte colony stimulating factors are indicated for decreasing the incidence of a fever neutropenia in patients with non-myeloid cancers who are undergoing myelosuppressive chemotherapy.

Guidelines recommended that G – CSF‘s are used prophylactically for FN patients with cancer receiving high risk chemotherapy regimen (20% or greater) or an intermediate risk (10 to 20%) regimen if greater than one risk factor is present.

Filgrastim and pegfilgastim are equally effective.

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