Febrile neutropenia

Resident Survival Guide

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

Synonyms and keywords: F and N; fever and neutropenia; FN; neutropenic fever; neutropenic fever syndrome

Overview

Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood. 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 (bacteria in the bloodstream) is present in approximately 20% of all patients with this condition.

Pathophysiology

A number of factors pose an increased risk for infection in patients with neutropenic fever:

• 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. In addition, patients receiving glucocorticoid-containing regimens, calcineurin inhibitors, or fludarabine are also predisposed to infection as a consequence of lymphocyte dysfunction.

• Altered microbiota

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

• 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.

• Immune defects associated with specific primary malignancies

An increased risk of infection has been observed in patients with Hodgkin's lymphoma (as a result of defects in cell-mediated immunity) and in patients with chronic lymphocytic leukemia or multiple myeloma (as a result of hypogammaglobulinemia).

Causes

Common Causes

• Cytotoxic chemotherapy

Causes by Organ System

Cardiovascular	No underlying causes
Chemical / poisoning	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Acyclovir, Albendazole, Allopurinol, Amantadine, Amiloride, Aminoglutethimide, Amiodarone, Ampicillin, Anakinra, Anidulafungin, Aprepitant, Aripiprazole, Arsenic trioxide, Asenapine, Atazanavir, Atovaquone, Auranofin, Azacitidine, Aztreonam, Belinostat, Benazepril, Bendamustine, Bevacizumab, Blinatumomab, Boceprevir, Bortezomib, Bosutinib, Brentuximab, Busulfan, Cabazitaxel, Cabozantinib, Canakinumab, Candesartan, Capecitabine, Captopril, Carboplatin, Carfilzomib, Cefaclor, Cefadroxil, Cefazolin, Cefepime, Cefixime, Cefoperazone, Cefotetan, Cefotiam, Cefoxitin, Ceftaroline, Ceftriaxone, Cefuroxime, Cephalexin, Cephapirin, Cephradine, Cetuximab, Chlorambucil, Chloroquine, Chlorpromazine, Chlorthalidone, Cidofovir, Cimetidine, Cladribine, Clarithromycin, Clindamycin, Clofarabine, Clopidogrel, Clozapine, Colchicine, Crizotinib, Cyclophosphamide, Cytarabine, Dabrafenib, Daclatasvir, Dactinomycin, Dasatinib, Decitabine, Deferasirox, Deferiprone, Delavirdine, Dexrazoxane, Diatrizoate, Diazepam, Diazoxide, Dicloxacillin, Diflunisal, Docetaxel, Dolutegravir, Doripenem, Doxorubicin, Doxycycline, Efavirenz, Elvitegravir, Enalapril, Enalaprilat, Enfuvirtide, Enzalutamide, Epirubicin, Eprosartan, Eribulin, Etanercept, Ethacrynic acid, Ethambutol, Etodolac, Etoposide, Everolimus, Fentanyl, Fidaxomicin, Fludarabine, Fluoxetine, Fosamprenavir, Foscarnet, Fosinopril, Ganciclovir, Gefitinib, Gemcitabine, Glyburide, Golimumab, Griseofulvin, Haloperidol, Ibritumomab, Ibrutinib, Ibuprofen, Idelalisib, Iloperidone, Imatinib, Imipenem cilastatin, Indomethacin, Infliximab, Interferon alfa-2a, Interferon alfa-2b, Interferon alfacon-1, Interferon beta-1b, Irinotecan, Isotretinoin, Itraconazole, Ixabepilone, Lamivudine, Lamotrigine, Lansoprazole, Lenalidomide, Levamisole, Levetiracetam, Lincomycin, Linezolid, Lisinopril, Loxapine, Lurasidone, Maprotiline, Maraviroc, Meclofenamate, Meropenem, Mesalamine, Methazolamide, Methotrexate, Methyldopa, Metolazone, Mexiletine, Mianserin, Micafungin, Mifamurtide, Minocycline, Mirtazapine, Mitotane, Mitoxantrone, Moexipril, Moxalactam, Mycophenolate, Mycophenolic acid, Nafcillin, Naproxen, Nefazodone, Nelarabine, Nelfinavir, Nevirapine, Nilotinib, Nilutamide, Norfloxacin, Obinutuzumab, Ofatumumab, Ofloxacin, Olanzapine, Olaparib, Omacetaxine, Omeprazole, Oxacillin, Oxaliplatin, Paclitaxel, Palbociclib, Paliperidone, Pantoprazole, Pazopanib, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed, Penicillin G, Pentamidine, Pentostatin, Peramivir, Perindopril, Pertuzumab, Phenytoin, Piperacillin, Piperaquine, Piroxicam, Pixantrone, Pomalidomide, Ponatinib, Posaconazole, Pralatrexate, Prednisone, Probenecid, Procainamide, Prochlorperazine, Quetiapine, Quinapril, Quinine, Radium chloride, Ramipril, Ramucirumab, Ranitidine, Rasburicase, Regorafenib, Ribavirin, Rifabutin, Rifapentine, Rifaximin, Rilonacept, Riluzole, Risperidone, Ritodrine, Ritonavir, Rituximab, Romidepsin, Ruxolitinib, Saquinavir, Satraplatin, Sirolimus, Sofosbuvir, Sorafenib, Stavudine, Succimer, Sulfasalazine, Sulindac, Sunitinib, Suramin, Tacrolimus, Tedizolid, Teicoplanin, Temozolomide, Temsirolimus, Teniposide, Tenofovir, Terbinafine, Teriflunomide, Thalidomide, Thiothixene, Ticarcillin, Ticlopidine, Tipranavir, Tocilizumab, Tofacitinib, Topotecan, Tositumomab, Trabectedin, Trametinib, Trandolapril, Trastuzumab, Trimethoprim, Valganciclovir, Valproic acid, Valrubicin, Valsartan, Vancomycin, Vandetanib, Vesnarinone, Vincristine, Vinflunine, Zidovudine, Ziprasidone, Ziv-Aflibercept, Zoledronic acid
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	No underlying causes
Musculoskeletal / Ortho	No underlying causes
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	No underlying causes

Causes in Alphabetical Order

The unnamed parameter 2= is no longer supported. Please see the documentation for {{columns-list}}.

3

Diagnosis

Diagnostic Criteria

The definitions of fever and neutropenia are used to identify patients in whom empirical antibiotic therapy must be initiated. However, neutropenic patients represent a heterogeneous population and treatment may be considered even when they do not meet these specific criteria. Additional parameters in risk assessment and clinical judgment also play a critical role in tailoring the management.

“

Fever 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.

”

“

Neutropenia 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.

”

“

Profound neutropenia Neutropenia in which the ANC is <100 cells/mm3; a manual reading of the blood smear is required to confirm this degree of neutropenia.

”

“

Functional neutropenia Functional neutropenia refers to patients whose hematologic malignancy results in qualitative defects (impaired phagocytosis and killing of pathogens) of circulating neutrophils. These patients should also be considered to be at increased risk for infection, despite a normal neutrophil count.

”

“

Microbiologically defined infection This can include both bacteremia, either with a single organism or polymicrobial infection, but without a definable nonhematogenous site of infection, and a microbiologically defined site of infection (e.g., pneumonia, cellulitis) with or without concomitant bacteremia.

”

“

Clinically defined infection This is designated when a site of infection is diagnosed (e.g., pneumonia,cellulitis) but its microbiologic pathogenesis either cannot be proven or is inaccessible to examination.

”

“

Unexplained fever In the neutropenic patient, this is defined as a new fever that is not accompanied by either clinical or microbiologic evidence of infection.

”

Multinational Association for Supportive Care in Cancer (MASCC) Risk Index

The Multinational Association for Supportive Care in Cancer (MASCC) Risk Index can be used to identify high-risk patients (score <21) and low-risk patients (score ≥21 points) for serious complications of febrile neutropenia (including death, intensive care unit admission, confusion, cardiac complications, respiratory failure, renal failure, hypotension, bleeding, and other serious medical complications). The score was developed to select patients for therapeutic strategies that could potentially be more convenient or cost-effective. The various variables and the weight of individual variables used in the MASCC risk index is as follows. To summarize, risk assessment helps determining the type of empirical antibiotic therapy, venue of the treatment, and duration of the antibiotic therapy.

Characteristic	Score
No or mild symptoms in patients following an episode of febrile neutropenia	5
Absence of hypotension with a systolic blood pressure >90 mmHg	5
No chronic obstructive pulmonary disease (active chronic bronchitis, emphysema, decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators)	4
Solid tumor or hematologic malignancy with no previously demonstrated fungal infection or empirically treated suspected fungal infection	4
Absence of dehydration that requires parenteral fluids	3
Moderate symptoms in patients following an episode of febrile neutropenia	3
Outpatient status	3
Age <60 years	2

A prospective trial demonstrated that a modified MASCC score can identify patients with febrile neutropenia at low risk of complications as well.

Treatment

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 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 recommend the use of particular combinations of antibiotics in specific settings; mild low-risk cases may be treated with a combination of oral co-amoxiclav and ciprofloxacin, while more severe cases require cephalosporins with activity against Pseudomonas aeruginosa (e.g. cefepime), or carbapenems (imipenem or meropenem). A subsequent meta-analysis published in 2006 found that cefepime was associated with more negative outcomes, and that carbapenems (while causing a higher rate of pseudomembranous colitis) were the most straightforward in use.

In 2010, an updated guidelines was issued by the Infectious Diseases Society of America, recommending use of cefepime, carbapenems (meropenem and imipenem/cilastatin), piperacillin/tazobactam for high risk patients and co-amoxiclav 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 treat as high risk patients.

See Also

• Neutropenia
• Leukopenia
• Fever
• Myelosuppression
• Chemotherapy

External Links

• Febrile neutropenia entry in the NCI Dictionary of Cancer Terms