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| {| class="infobox" style="float: right;" | | {{Siren|Febrile neutropenia}} |
| | style="vertical-align: middle; padding: 5px;" align=center | [[File:Siren.gif|30px|link=Febrile neutropenia resident survival guide]]
| | {{Febrile neutropenia}} |
| | style="vertical-align: middle; padding: 5px;" align=center | [[Febrile neutropenia resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']]
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| |}
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| {{CMG}} | | {{CMG}} |
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| {{SK}} F and N; fever and neutropenia; FN; neutropenic fever; neutropenic fever syndrome | | {{SK}} F and N; fever and neutropenia; FN; hot and low; hot leuk; neutropenic fever; neutropenic fever syndrome; neutropenic sepsis |
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| == Overview == | | ==[[Febrile neutropenia overview|Overview]]== |
| '''Febrile neutropenia''' is a condition characterized by a decrease in neutrophils (neutropenia) associated with fever, the latter indicating the presence of an infection.<ref>{{Cite web | title = NCI Thesaurus | accessdate = | url = http://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C35665&ns=NCI_Thesaurus }}</ref> The majority of patients have no identifiable site of infection and no positive culture results. Nonetheless, urgent therapy with empirical antibiotics is recommended in light of the possibility of rapid progression.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
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| == Historical Perspective == | | ==[[Febrile neutropenia historical perspective|Historical Perspective]]== |
| 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.<ref>{{Cite journal | issn = 0003-4819 | volume = 64 | issue = 2 | pages = 328–340 | last = Bodey | first = G. P. | coauthors = M. Buckley, Y. S. Sathe, E. J. Freireich | title = Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia | journal = Annals of Internal Medicine | date = 1966-02 | pmid = 5216294 }}</ref> Infection risk begins to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm<sup>3</sup> and rises markedly when the ANC drops to less than 500 cells/mm<sup>3</sup>. 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.<ref>{{Cite journal | issn = 0025-7974 | volume = 61 | issue = 3 | pages = 153–165 | last = Pizzo | first = P. A. | coauthors = K. J. Robichaud, R. Wesley, J. R. Commers | title = Fever in the pediatric and young adult patient with cancer. A prospective study of 1001 episodes | journal = Medicine | date = 1982-05 | pmid = 7078399 }}</ref>
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| == Pathophysiology == | | ==[[Febrile neutropenia pathophysiology|Pathophysiology]]== |
| A number of factors pose an increased risk for infection in patients with neutropenic fever:
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| * '''Absolute or functional leukopenia'''
| | ==[[Febrile neutropenia causes|Causes]]== |
| :: [[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.
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| * '''Altered microbiota'''
| | ==[[Febrile neutropenia epidemiology and demographics|Epidemiology and Demographics]]== |
| :: [[Microbiome|Microbiota]] that inhabit the skin, respiratory tract, and digestive tract may be altered by cancer and its treatment or the use of antibiotics.<ref>{{Cite journal | doi = 10.1056/NEJMct1210890 | issn = 1533-4406 | volume = 368 | issue = 12 | pages = 1131–1139 | last = Bennett | first = Charles L. | coauthors = Benjamin Djulbegovic, LeAnn B. Norris, James O. Armitage | title = Colony-stimulating factors for febrile neutropenia during cancer therapy | journal = The New England Journal of Medicine | date = 2013-03-21 | pmid = 23514290 | pmc = PMC3947590 }}</ref>
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| * '''Breaches of natural barriers'''
| | ==[[Febrile neutropenia risk factors|Risk Factors]]== |
| :: [[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 [[commensal]]s into blood or subcutaneous tissues or serve as a [[biofilm]] which bacteria can colonize.
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| * '''Immune defects associated with specific primary malignancies'''
| | ==[[Febrile neutropenia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| :: 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]]).
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| == Causes == | | ==Diagnosis== |
| {| style="float: right; width: 500px; margin: 5px 10px;"
| | [[Febrile neutropenia diagnostic criteria|Diagnostic Criteria]] | [[Febrile neutropenia initial assessment|Initial Assessment]] | [[Febrile neutropenia history and symptoms|History and Symptoms]] | [[Febrile neutropenia physical examination|Physical Examination]] | [[Febrile neutropenia laboratory findings|Laboratory Findings]] | [[Febrile neutropenia CT|CT]] | [[Febrile neutropenia other diagnostic studies|Other Diagnostic Studies]] |
| ! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" | Table 1. Common Bacterial Pathogens in Neutropenic Patients
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| ! style="font-size: 85%; background: #DCDCDC;" | Gram-Positive Pathogens
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| | style="font-size: 85%; background: #F5F5F5;" | | |
| :* Coagulase-negative staphylococci
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| :* Staphylococcus aureus, including methicillin-resistant strains
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| :* Enterococcus species, including vancomycin-resistant strains
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| :* Viridans group streptococci
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| :* Streptococcus pneumoniae
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| :* Streptococcus pyogenes
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| |- | |
| ! style="font-size: 85%; background: #DCDCDC;" | Gram-Negative Pathogens
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| | style="font-size: 85%; background: #F5F5F5;" | | |
| :* Escherichia coli
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| :* Klebsiella species
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| :* Enterobacter species
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| :* Pseudomonas aeruginosa
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| :* Citrobacter species
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| :* Acinetobacter species
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| :* Stenotrophomonas maltophilia
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| |} | |
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| Bloodstream infections caused by endogenous flora and reactivation of latent infections account for a majority of initial febrile episode in neutropenic patients with cancer. Common bacterial isolates that cause bacteremia in the setting of neutropenia are listed in Table 1.<ref>{{Cite journal | doi = 10.1007/s00277-011-1373-2 | issn = 1432-0584 | volume = 91 | issue = 5 | pages = 767–774 | last = Pagano | first = L. | coauthors = M. Caira, G. Rossi, M. Tumbarello, R. Fanci, M. G. Garzia, N. Vianelli, N. Filardi, P. De Fabritiis, A. Beltrame, M. Musso, A. Piccin, A. Cuneo, C. Cattaneo, T. Aloisi, M. Riva, G. Rossi, U. Salvadori, M. Brugiatelli, S. Sannicolò, M. Morselli, A. Bonini, P. Viale, A. Nosari, F. Aversa, Hema e-Chart Group, Italy | title = A prospective survey of febrile events in hematological malignancies | journal = Annals of Hematology | date = 2012-05 | pmid = 22124621 }}</ref> 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 multiresistant bacteria.<ref>{{Cite book | edition = 5 edition | publisher = Saunders | isbn = 9781455728657 | last = MD | first = John E. Niederhuber | coauthors = James O. Armitage MD, James H. Doroshow MD, Michael B. Kastan MD PhD, Joel E. Tepper MD | title = Abeloff's Clinical Oncology: Expert Consult Premium Edition - Enhanced Online Features and Print, 5e | location = Philadelphia, Pennsylvania | date = 2013-11-05 }}</ref>
| | == Treatment == |
| | [[Febrile neutropenia medical therapy|Medical Therapy]] | [[Febrile neutropenia primary prevention|Primary Prevention]] |
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| 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.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
| | == Guideline Sources == |
| | * Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref> |
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| == Epidemiology and Demographics ==
| | * Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline<ref>{{Cite journal | doi = 10.1200/JCO.2012.45.8661 | issn = 1527-7755 | volume = 31 | issue = 6 | pages = 794–810 | last = Flowers | first = Christopher R. | coauthors = Jerome Seidenfeld, Eric J. Bow, Clare Karten, Charise Gleason, Douglas K. Hawley, Nicole M. Kuderer, Amelia A. Langston, Kieren A. Marr, Kenneth V. I. Rolston, Scott D. Ramsey | title = Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline | journal = Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology | date = 2013-02-20 | pmid = 23319691 }}</ref> |
| 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.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
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| 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.<ref>{{Cite journal | doi = 10.1086/383048 | issn = 1537-6591 | volume = 39 Suppl 1 | pages = –25-31 | last = Ramphal | first = Reuben | title = Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2004-07-15 | pmid = 15250017 }}</ref>
| | * Guideline for the Management of Fever and Neutropenia in Children with Cancer and/or Undergoing Hematopoietic Stem-Cell Transplantation: American Society of Clinical Oncology Endorsement<ref>{{Cite journal | doi = 10.1200/JCO.2012.42.7161 | issn = 1527-7755 | volume = 30 | issue = 35 | pages = 4427–4438 | last = Lehrnbecher | first = Thomas | coauthors = Robert Phillips, Sarah Alexander, Frank Alvaro, Fabianne Carlesse, Brian Fisher, Hana Hakim, Maria Santolaya, Elio Castagnola, Bonnie L. Davis, L. Lee Dupuis, Faith Gibson, Andreas H. Groll, Aditya Gaur, Ajay Gupta, Rejin Kebudi, Sérgio Petrilli, William J. Steinbach, Milena Villarroel, Theoklis Zaoutis, Lillian Sung, International Pediatric Fever and Neutropenia Guideline Panel | title = Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation | journal = Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology | date = 2012-12-10 | pmid = 22987086 }}</ref> |
| <!--
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| == Risk Factors ==
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| == Natural History, Complications and Prognosis ==
| | * Prevention and Treatment of Cancer-Related Infections: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology<ref>{{Cite web | title = Prevention and Treatment of Cancer-Related Infections | accessdate = | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref> |
| -->
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| == Diagnosis ==
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| === Diagnostic Criteria ===
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| 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. Clinical judgment based on parameters in risk assessment also plays a critical role in tailoring the management.
| | * Management of Febrile Neutropenia: European Society for Medical Oncology Clinical Recommendations<ref>{{Cite journal | doi = 10.1093/annonc/mdp163 | issn = 1569-8041 | volume = 20 Suppl 4 | pages = 166–169 | last = Marti | first = F. Marti | coauthors = M. H. Cullen, F. Roila, ESMO Guidelines Working Group | title = Management of febrile neutropenia: ESMO clinical recommendations | journal = Annals of oncology: official journal of the European Society for Medical Oncology / ESMO | date = 2009-05 | pmid = 19454445 }}</ref> |
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| ==== Fever ==== | | == References == |
| 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.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
| | {{reflist|2}} |
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| ==== Neutropenia ==== | | == Related Chapters == |
| Neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm<sup>3</sup> or an ANC that is expected to decrease to <500 cells/mm<sup>3</sup> during the next 48 hours.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
| | *[[Chemotherapy]] |
| | | *[[Fever]] |
| ==== Profound neutropenia ====
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| Neutropenia in which the ANC is <100 cells/mm<sup>3</sup>; a manual reading of the blood smear is required to confirm this degree of neutropenia.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
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| ==== Functional neutropenia ====
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| 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.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
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| ==== Microbiologically defined infection ====
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| This can include both
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| # bacteremia, either with a single organism or polymicrobial infection, but without a definable nonhematogenous site of infection, and
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| # a microbiologically defined site of infection (e.g., pneumonia, cellulitis) with or without concomitant bacteremia.<ref>{{Cite journal | issn = 0022-1899 | volume = 161 | issue = 3 | pages = 397–401 | title = From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel | journal = The Journal of Infectious Diseases | date = 1990-03 | pmid = 2179421 }}</ref>
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| ==== Clinically defined infection ====
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| 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.<ref>{{Cite journal | issn = 0022-1899 | volume = 161 | issue = 3 | pages = 397–401 | title = From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel | journal = The Journal of Infectious Diseases | date = 1990-03 | pmid = 2179421 }}</ref>
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| ==== Unexplained fever ====
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| In the neutropenic patient, this is defined as a new fever that is not accompanied by either clinical or microbiologic evidence of infection.<ref>{{Cite journal | issn = 0022-1899 | volume = 161 | issue = 3 | pages = 397–401 | title = From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel | journal = The Journal of Infectious Diseases | date = 1990-03 | pmid = 2179421 }}</ref>
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| === History ===
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| Pertinent history should include new site-specific symptoms, prior use of antimicrobial agents, potential infection exposures, previous documented infections or pathogen colonization, catheter 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.
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| === Signs and Symptoms ===
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| In neutropenic patients, manifestations secondary to inflammation are attenuated and fever is often the only clue indicative of an underlying infection.
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| === Physical Examination ===
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| The physical examination should focus on potential sites of infection.
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| ==== Skin ====
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| Induration and erythema may be minimal. Pustule formation are uncommon in the absence of neutrophils.
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| ==== Throat ====
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| 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.
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| ==== Lungs ====
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| Auscultation of the lungs may reveal minimal adventitial sounds.
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| ==== Abdomen ====
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| Abdominal pain in neutropenic patients may herald an intraabdominal catastrophe secondary to neutropenic enterocolitis or tumor necrosis.
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| ==== Other ====
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| Examination of catheter sites may disclose erythema, tenderness, or discharge.
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| === Laboratory Findings ===
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| ==== Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Initial Assessment ====
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| {| class="wikitable" style="width: 80%;"
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| | colspan="1" style="text-align:center; background: LightGreen;"| [[IDSA guidelines classification scheme#Strength of Recommendations|Class A]]
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| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''1.''' Laboratory tests should include a CBC count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
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| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''2.''' At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing CVC, if present, and from a peripheral vein site; 2 blood culture sets from separate venipunctures should be sent if no central catheter is present. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
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| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''3.''' Culture specimens from other sites of suspected infection should be obtained as clinically indicated. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
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| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''4.''' A chest radiograph is indicated for patients with respiratory signs or symptoms. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
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| |}
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| {| class="wikitable" style="width: 80%;"
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| | colspan="1" style="text-align:center; background: LightCoral;"| [[IDSA guidelines classification scheme#Strength of Recommendations|Class C]]
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| |bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' Blood culture volumes should be limited to <1% of total blood volume (usually ~70 mL/kg) in patients weighing <40 kg. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
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| == Risk Assessment ==
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| {| style="float: right; width: 500px; margin: 5px 10px;"
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| ! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" colspan=2 | Table 2. Medical Complications Considered Serious
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| | style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" colspan=2 |
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| * Hypotension: systolic blood pressure less than 90 mmHg or need for pressor support to maintain blood pressure
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| * Respiratory failure: arterial oxygen pressure less than 60 mmHg while breathing room air or need for mechanical ventilation Intensive care unit admission
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| * Disseminated intravascular coagulation
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| * Confusion or altered mental state
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| * Congestive cardiac failure seen on chest x-ray and requiring treatment
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| * Bleeding severe enough to require transfusion
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| * Arrhythmia or ECG changes requiring treatment
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| * Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention
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| * Other complications judged serious and clinically significant by the investigator<sup>†</sup>
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| | style="font-size: 85%; background: #F5F5F5; padding: 5px 10px;" colspan=2 |
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| <sup>†</sup> 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.
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| ! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" colspan=2 | Table 3. MASCC Risk Index Score
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| | style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" |
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| Characteristic
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| : Burden of febrile neutropenia with no or mild symptoms<sup>a</sup>
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| : No hypotension (systolic blood pressure >90 mmHg)
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| : No chronic obstructive pulmonary disease<sup>b</sup>
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| : Solid tumor or hematologic malignancy w/o prior fungal infection<sup>c</sup>
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| : No dehydration requiring parenteral fluids
| |
| : Burden of febrile neutropenia with moderate symptoms<sup>a</sup>
| |
| : Outpatient status
| |
| : Age <60 years
| |
| | style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" |
| |
| Weight
| |
| <div style="text-align: center; font-weight: bold;">5</div>
| |
| <div style="text-align: center; font-weight: bold;">5</div>
| |
| <div style="text-align: center; font-weight: bold;">4</div>
| |
| <div style="text-align: center; font-weight: bold;">4</div>
| |
| <div style="text-align: center; font-weight: bold;">3</div>
| |
| <div style="text-align: center; font-weight: bold;">3</div>
| |
| <div style="text-align: center; font-weight: bold;">3</div>
| |
| <div style="text-align: center; font-weight: bold;">2</div>
| |
| |-
| |
| | style="font-size: 85%; background: #F5F5F5; padding: 5px 10px;" colspan=2 |
| |
| The maximum value of the score is 26. <sup>a</sup> 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. <sup>b</sup> 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. <sup>c</sup> Previous fungal infection means demonstrated fungal infection or empirically treated suspected fungal infection.
| |
| |}
| |
| | |
| [[Infectious Diseases Society of America| Infectious Diseases Society of America (IDSA)]] recommends that either the clinical judgment criteria or the MASCC assessment tool can be used to stratify risk for patients presenting with fever and neutropenia. Risk 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.
| |
| | |
| === Clinical Judgment Criteria ===
| |
| Patients with febrile neutropenia can be stratified at presentation into those with '''high-risk''' versus '''low-risk''' for complications of severe infection by the clinical judgment criteria as follows:<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
| |
| | |
| ==== High-Risk Patient by Clinical Judgment Criteria ====
| |
| Patients with <u>any</u> of the following criteria are considered to be at '''high risk''' for serious complications during fever and neutropenia:
| |
| * Profound neutropenia (ANC ≤100 cells/mm<sup>3</sup>) anticipated to extend >7 days
| |
| * Presence of any co-morbid medical problems including but not limited to:
| |
| :* Hemodynamic instability
| |
| :* Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea
| |
| :* Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea
| |
| :* Neurologic or mental-status changes of new onset d Intravascular catheter infection, especially catheter tunnel infection
| |
| :* New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease
| |
| * Evidence of hepatic insufficiency (defined as aminotransferase levels greater than 5 times of normal values) or renal insufficiency (defined as a creatinine clearance of less than 30 mL/min).
| |
| | |
| High-risk patients should be hospitalized and receive intravenous empirical antibiotic therapy.
| |
| | |
| ==== Low-Risk Patient by Clinical Judgment Criteria ====
| |
| Patients with <u>all</u> of the following criteria are considered to be at '''low risk''' for serious complications during fever and neutropenia:
| |
| * Neutropenia expected to resolve within 7 days
| |
| * No active medical co-morbidity
| |
| * Stable and adequate hepatic function and renal function. | |
| | |
| In general, any patient who does not strictly fulfill criteria for being at low risk should be treated according to guidelines for high-risk patients. Low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.
| |
| <!--
| |
| * '''High-risk''' patients refer to those who
| |
| :* have sustained, profound neutropenia anticipated to last >1 week or,
| |
| :* are clinically unstable (eg, experience uncontrolled pain, altered mental status, or hypotension) or,
| |
| :* have significant medical co-morbidities, such as uncontrolled cancer, chronic obstructive pulmonary disease, poor functional status, or advanced age.
| |
| :* High-risk patients also may be identified by underlying cancer (eg, acute leukemia) and/or the intensity of chemotherapy undergone (eg, induction for acute leukemia or HSCT).
| |
| * '''Low-risk''' patients are clinically defined by neutropenia anticipated to last ≤7 days, are clinically stable, and have no medical comorbid conditions.
| |
| -->
| |
| === Multinational Association for Supportive Care in Cancer (MASCC) Risk Index ===
| |
| | |
| The MASCC scoring system is a summation of weighted factors, including patient age, history, outpatient or inpatient status, acute clinical signs, the presence of medical comorbid conditions, and severity of fever and neutropenia as assessed by burden of illness. The MASCC Risk Index can be used to identify subgroups of febrile neutropenic patients with '''high-risk (score <21)''' or '''low-risk (score ≥21)''' for serious complications and death (Table 2 and Table 3). It is also a means to determine which patients require prolonged hospitalization and which may be candidates for oral or once-daily IV regimens and/or for early discharge from the hospital to complete the antibiotic course as outpatients.<ref>{{Cite journal | issn = 0732-183X | volume = 18 | issue = 16 | pages = 3038–3051 | last = Klastersky | first = J. | coauthors = M. Paesmans, E. B. Rubenstein, M. Boyer, L. Elting, R. Feld, J. Gallagher, J. Herrstedt, B. Rapoport, K. Rolston, J. Talcott | title = The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients | journal = Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology | date = 2000-08 | pmid = 10944139 }}</ref> A fundamental difficulty with the MASCC Risk Index is the indistinct nature of its major criteria: the "burden of febrile neutropenia" and associated symptoms. Without a clear standardized definition of this ‘‘burden’’ of disease, uniform application of the MASCC Risk Index may be confusing.<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
| |
| | |
| ==== Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Risk Assessment ====
| |
| | |
| {| class="wikitable" style="width: 80%;"
| |
| |-
| |
| | colspan="1" style="text-align:center; background: LightGreen;"| [[IDSA guidelines classification scheme#Strength of Recommendations|Class A]]
| |
| |-
| |
| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''1.''' Assessment of risk for complications of severe infection should be undertaken at presentation of fever. Risk assessment may determine the type of empirical antibiotic therapy (oral vs IV), venue of treatment (inpatient vs outpatient), and duration of antibiotic therapy. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
| |
| |-
| |
| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''2.''' Most experts consider high-risk patients to be those with anticipated prolonged (>7 days duration) and profound neutropenia (absolute neutrophil count [ANC] ≤100 cells/mm<sup>3</sup> following cytotoxic chemotherapy) and/or significant medical co-morbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. Such patients should be initially admitted to the hospital for empirical therapy. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
| |
| |-
| |
| | bgcolor="LightGreen"| <nowiki>"</nowiki>'''3.''' Low-risk patients, including those with anticipated brief (≤7 days duration) neutropenic periods or no or few co-morbidities, are candidates for oral empirical therapy. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
| |
| |}
| |
| | |
| {| class="wikitable" style="width: 80%;"
| |
| |-
| |
| | colspan="1" style="text-align:center; background: LemonChiffon;"| [[IDSA guidelines classification scheme#Strength of Recommendations|Class B]]
| |
| |-
| |
| |bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' Formal risk classification may be performed using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<BR> i. High-risk patients have a MASCC score <21. All patients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients. <BR> ii. Low-risk patients have a MASCC score ≥21. Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.<nowiki>"</nowiki>
| |
| |}
| |
| | |
| == Treatment ==
| |
| Generally, patients with febrile neutropenia are treated with empirical [[antibiotic]]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]] 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 [[cephalosporin]]s with activity against ''[[Pseudomonas aeruginosa]]'' (e.g. [[cefepime]]), or [[carbapenem]]s ([[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.<ref name="pmid16344285">{{cite journal |author=Paul M, Yahav D, Fraser A, Leibovici L |title=Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials |journal=J. Antimicrob. Chemother. |volume=57 |issue=2 |pages=176–89 |year=2006 |pmid=16344285 |doi=10.1093/jac/dki448|url=http://jac.oxfordjournals.org/cgi/content/full/57/2/176 |month= February|issn=0305-7453}}</ref>
| |
| | |
| 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.
| |
| | |
| ==Guideline Sources==
| |
| * Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America<ref>{{Cite journal | doi = 10.1093/cid/ciq147 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = 427–431 | last = Freifeld | first = Alison G. | coauthors = Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard, null Infectious Diseases Society of Americaa | title = Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = 2011-02-15 | pmid = 21205990 }}</ref>
| |
| | |
| == See Also ==
| |
| *[[Neutropenia]] | |
| *[[Leukopenia]] | | *[[Leukopenia]] |
| *[[Fever]]
| |
| *[[Myelosuppression]] | | *[[Myelosuppression]] |
| *[[Chemotherapy]] | | *[[Neutropenia]] |
| | |
| ==References==
| |
| {{Reflist|2}}
| |
|
| |
|
| ==External Links== | | == External Links == |
| * [http://www.cancer.gov/dictionary?CdrID=415543 Febrile neutropenia] entry in the NCI Dictionary of Cancer Terms | | * [http://www.cancer.gov/dictionary?CdrID=415543 Febrile neutropenia entry in the NCI Dictionary of Cancer Terms] |
