Febrile neutropenia: Difference between revisions

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{{Siren|Febrile neutropenia}}
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{{Febrile neutropenia}}
| style="vertical-align: middle; padding: 5px;" align=center | [[Febrile neutropenia resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']]
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{{SK}} F and N; fever and neutropenia; FN; hot and low; hot leuk; neutropenic fever; neutropenic fever syndrome; neutropenic sepsis
{{SK}} F and N; fever and neutropenia; FN; hot and low; hot leuk; neutropenic fever; neutropenic fever syndrome; neutropenic sepsis


== Overview ==
==[[Febrile neutropenia overview|Overview]]==
'''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]].<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 treatment 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>


== 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>


== Pathophysiology ==
==[[Febrile neutropenia pathophysiology|Pathophysiology]]==
A number of factors pose an increased risk for infections in cancer patients:


* '''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.


* '''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> 


* '''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.  Solid tumors that overgrow their blood supply may undergo necrosis and form a nidus for infection.


* '''Immune defects associated with specific primary malignancies'''
==[[Febrile neutropenia natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
:: 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]]''.<ref>{{Cite journal | issn = 0009-9104 | volume = 89 | issue = 3 | pages = 374–377 | last = Griffiths | first = H. | coauthors = J. Lea, C. Bunch, M. Lee, H. Chapel | title = Predictors of infection in chronic lymphocytic leukaemia (CLL) | journal = Clinical and Experimental Immunology | date = 1992-09 | pmid = 1516254 | pmc = PMC1554487 }}</ref><ref>{{Cite journal | issn = 0003-4819 | volume = 96 | issue = 1 | pages = 47–50 | last = Savage | first = D. G. | coauthors = J. Lindenbaum, T. J. Garrett | title = Biphasic pattern of bacterial infection in multiple myeloma | journal = Annals of Internal Medicine | date = 1982-01 | pmid = 6976144 }}</ref>  An increased risk of infection has also been observed in patients with [[Hodgkin's lymphoma]] as a result of defective [[cell-mediated immunity]].


* '''Hyposplenism'''
==Diagnosis==
:: Production of [[opsonization|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.
[[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]]
 
* '''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]].<ref>{{Cite journal | issn = 0003-4819 | volume = 129 | issue = 7 | pages = 559–566 | last = Anaissie | first = E. J. | coauthors = D. P. Kontoyiannis, S. O'Brien, H. Kantarjian, L. Robertson, S. Lerner, M. J. Keating | title = Infections in patients with chronic lymphocytic leukemia treated with fludarabine | journal = Annals of Internal Medicine | date = 1998-10-01 | pmid = 9758577 }}</ref>  Therapy with [[alemtuzumab]], a humanized monoclonal antibody targeting [[CD52]] on lymphocytes, heightened the risk for a wide variety of infections.<ref>{{Cite journal | doi = 10.1200/JCO.2005.04.021 | issn = 0732-183X | volume = 23 | issue = 13 | pages = 2971–2979 | last = Moreton | first = Paul | coauthors = Ben Kennedy, Guy Lucas, Michael Leach, Saad M. B. Rassam, Andrew Haynes, Jane Tighe, David Oscier, Christopher Fegan, Andy Rawstron, Peter Hillmen | title = Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival | journal = Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology | date = 2005-05-01 | pmid = 15738539 }}</ref><ref>{{Cite journal | doi = 10.1111/j.1365-2141.2005.05789.x | issn = 0007-1048 | volume = 132 | issue = 1 | pages = 3–12 | last = Thursky | first = Karin A. | coauthors = Leon J. Worth, John F. Seymour, H. Miles Prince, Monica A. Slavin | title = Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab* | journal = British Journal of Haematology | date = 2006-01 | pmid = 16371014 }}</ref><ref>{{Cite journal | issn = 0006-4971 | volume = 99 | issue = 10 | pages = 3554–3561 | last = Keating | first = Michael J. | coauthors = Ian Flinn, Vinay Jain, Jacques-Louis Binet, Peter Hillmen, John Byrd, Maher Albitar, Lee Brettman, Pedro Santabarbara, Bret Wacker, Kanti R. Rai | title = Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal = Blood | date = 2002-05-15 | pmid = 11986207 }}</ref>  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.<ref>{{Cite web | last = | first = | title = Drug Safety and Availability - FDA Drug Safety Communication: Boxed Warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) | format = WebContent | accessdate =  | url = http://www.fda.gov/Drugs/DrugSafety/ucm366406.htm }}</ref>
 
== Causes ==
{| style="float: right; width: 500px; margin: 5px 10px;"
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" | Table 1. Common Bacterial Pathogens in Neutropenic Patients
|-
! style="font-size: 85%; background: #DCDCDC;" | Gram-Positive Pathogens
|-
| style="font-size: 85%; background: #F5F5F5;" |
:* Coagulase-negative staphylococci
:* Staphylococcus aureus, including methicillin-resistant strains
:* Enterococcus species, including vancomycin-resistant strains
:* Viridans group streptococci
:* Streptococcus pneumoniae
:* Streptococcus pyogenes
|-
! style="font-size: 85%; background: #DCDCDC;" | Gram-Negative Pathogens
|-
| style="font-size: 85%; background: #F5F5F5;" |
:* Escherichia coli
:* Klebsiella species
:* Enterobacter species
:* Pseudomonas aeruginosa
:* Citrobacter species
:* Acinetobacter species
:* Stenotrophomonas maltophilia
|}
 
{{Seealso|Neutropenia causes}}
 
[[Septicemia|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]], [[HBV|hepatitis B]] and [[HCV|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.<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>
 
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>
 
== Epidemiology and Demographics ==
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>
 
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>
 
== Risk Factors ==
{{Seealso|Antimicrobial Prophylaxis for Cancer-Related Infections}}
 
=== NCCN Overall Infection Risk Categories ===
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.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>
 
==== Low risk for infectious complications ====
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 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.
 
==== High risk for infectious complications ====
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.
 
== Complications ==
{| style="float: right; width: 500px; margin: 5px 10px;"
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" | Table 2. Medical Complications Considered Serious
|-
| style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" colspan=2 |
* 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<sup>†</sup>
|-
| style="font-size: 85%; background: #F5F5F5; padding: 5px 10px;" |
<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.
|}
 
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).<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>
 
== 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.  Clinical judgment based on parameters in risk assessment also plays 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.<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>
 
==== Neutropenia ====
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>
 
==== Profound neutropenia ====
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>
 
==== 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.<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>
 
==== 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.<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>
 
==== 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.<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>
 
==== 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.<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>
 
=== History ===
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.
 
=== Signs and Symptoms ===
In neutropenic patients, manifestations secondary to inflammation are attenuated and fever is often the only clue indicative of an underlying infection.
 
=== Physical Examination ===
The physical examination should focus on potential sites of infection.
 
==== Skin ====
Induration and erythema may be minimal.  Pustule formation are uncommon in the absence of neutrophils.
 
==== Throat ====
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.
 
==== Lungs ====
Auscultation of the lungs may reveal minimal adventitial sounds.
 
==== Abdomen ====
Abdominal pain in neutropenic patients may herald an intraabdominal catastrophe secondary to neutropenic enterocolitis or tumor necrosis.
 
==== Other ====
Examination of catheter sites may disclose erythema, tenderness, or discharge.
 
=== Laboratory Tests ===
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.  These tests should be performed at least every 3 days during the initial course of antibiotic treatment. At least weekly monitoring of transaminase levels is advisable for patients with suspected hepatocellular injury or cholestatic disease.  Routine test of inflammation markers, such as C-reactive protein, IL-6, IL-8, or procalcitonin, to guide clinical decisions is not recommended.
 
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. In pediatric patients, the total sample limit would be 7 mL for a 10-kg patient and 28 mL for a 40-kg patient.  Drawing blood samples from both peripheral vein and catheter may help determine the source of infection.  Culture for coagulase-negative staphylococci requires two positive results to be considered a "true positive."  After initial defervescence occurs with empirical treatment, any recrudescent fever should be evaluated as a new episode of possible infection.<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>
 
==== Stool ====
A stool specimen in a patient with diarrhea should be evaluated with Clostridium difficile toxin assays. There is limited value in sending a stool specimen for bacterial pathogen cultures or for ova and parasite examination for most patients unless there has been recent travel to or residence in areas of endemicity.<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>
 
==== Urine  ====
Culture of urine samples is indicated if signs or symptoms of urinary tract infection exist, a urinary catheter is in place, or the findings of urinalysis are abnormal.<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>
 
==== Cerebrospinal Fluid ====
Examination and culture of the cerebrospinal fluid is indicated if meningitis is suspected. Platelet transfusion may be considered prior to lumbar puncture if thrombocytopenia is a concern.<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>
 
==== Skin Biopsy ====
Biopsy of skin lesions suspected of infection should be performed for Gram staining and culture.<ref>{{Cite journal | issn = 0002-922X | volume = 140 | issue = 5 | pages = 459–461 | last = Allen | first = U. | coauthors = C. R. Smith, C. G. Prober | title = The value of skin biopsies in febrile, neutropenic, immunocompromised children | journal = American Journal of Diseases of Children (1960) | date = 1986-05 | pmid = 3962940 }}</ref>
 
==== Respiratory Specimens ====
Sputum samples for routine bacterial culture should be obtained from patients with productive cough. Specimens obtained by bronchoalveolar lavage (BAL) are recommended for patients with a pulmonary infiltrate of uncertain etiology.  Polymerase chain reaction testing, rapid antigen testing, or culture on nasal wash or BAL samples should be performed for respiratory viruses (including adenovirus, influenza A and B virus, respiratory syncytial virus, and parainfluenza virus) in patients with suggestive signs or symptoms during the winter season.<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>
 
=== Imaging Studies ===
Chest radiography should be reserved for patients with symptoms of respiratory tract infection.  CT scan of the head, sinuses, abdomen, and pelvis may be performed if clinically indicated.<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>
 
==== IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Initial 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.''' 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>
|-
| 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>
|-
| 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>
|-
| 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>
|}
 
{| class="wikitable" style="width: 80%;"
|-
| colspan="1" style="text-align:center; background: LightCoral;" | [[IDSA guidelines classification scheme#Strength of Recommendations|Class C]]
|-
|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>
|}
 
== Risk Assessment ==
{| style="float: right; width: 500px; margin: 5px 10px;"
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" colspan=2 | Table 3. MASCC Risk Index Score
|-
| style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" |
Characteristic
: Burden of febrile neutropenia with no or mild symptoms<sup>a</sup>
: No hypotension (systolic blood pressure >90 mmHg)
: No chronic obstructive pulmonary disease<sup>b</sup>
: Solid tumor or hematologic malignancy w/o prior fungal infection<sup>c</sup>
: 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.
 
=== MASCC Risk Index ===
The Multinational Association for Supportive Care in Cancer (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 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>
 
==== 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 ==
== 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.
[[Febrile neutropenia medical therapy|Medical Therapy]] | [[Febrile neutropenia primary prevention|Primary Prevention]]
 
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.
 
==== IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antibiotic Therapy ====
{| 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.''' High-risk patients require hospitalization for IV empirical antibiotic therapy; monotherapy with an anti- pseudomonal b-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''2.''' Vancomycin (or other agents active against aerobic gram- positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia (A-I). These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''3.''' Most penicillin-allergic patients tolerate cephalosporins, but those with a history of an immediate-type hypersensitivity reaction (eg, hives and bronchospasm) should be treated with a combination that avoids b-lactams and carbapenems, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''4.''' Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting; they may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria. Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''5.''' Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''6.''' Hospital re-admission or continued stay in the hospital is required for persistent fever or signs and symptoms of worsening infection. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''7.''' Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''8.''' Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''9.''' Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''10.''' If vancomycin or other coverage for gram-positive organisms was started initially, it may be stopped after 2 days if there is no evidence for a gram-positive infection. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''11.''' Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''12.''' Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable. An IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''13.''' If fever persists or recurs within 48 h in outpatients, hospital re-admission is recommended, with management as for high-risk patients. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''14.''' Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4–7 days of a broad-spectrum antibacterial regimen and no identified fever source. ''([[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: LightCoral;" | [[IDSA guidelines classification scheme#Strength of Recommendations|Class C]]
|-
|bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' KPCs: Consider early use of polymyxin-colistin or tigecycline. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
 
|bgcolor="LightCoral"|<nowiki>"</nowiki>'''2.''' Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>


|}
== Guideline Sources ==
 
{| 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.''' Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood culture results suspicious for resistant bacteria. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki> <BR> i. MRSA: Consider early addition of vancomycin, linezolid, or daptomycin <BR> ii. VRE: Consider early addition of linezolid or daptomycin <BR> iii. ESBLs: Consider early use of a carbapenem
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''3.''' Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''4.''' Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''5.''' Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''6.''' In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC is ≥500 cells/mm<sup>3</sup>) or longer if clinically necessary. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
 
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''7.''' In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery; the traditional endpoint is an increasing ANC that exceeds 500 cells/mm<sup>3</sup>. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|}
 
== Prophylaxis ==
{| style="float: right; width: 500px; margin: 5px 10px;"
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" colspan=2 | Table 4. Antimicrobial Prophylaxis for Cancer-Related Infections
|-
! style="font-size: 85%; background: #DCDCDC;" colspan=2 | Low Risk
|-
| style="font-size: 85%; background: #F5F5F5;" colspan=2 |
:* Bacterial - None
:* Fungal - None
:* Viral - None except positive HSV serology
|-
! style="font-size: 85%; background: #DCDCDC;" colspan=2 | Intermediate Risk
|-
| style="font-size: 85%; background: #F5F5F5;" colspan=2 |
:* Bacterial - Consider fluoroquinolone prophylaxis
:* Fungal - Consider antifungals during neutropenia and for anticipated mucositis
:* Viral - During neutropenia and at least 30 days after HSCT
|-
! style="font-size: 85%; background: #DCDCDC;" colspan=2 | High Risk
|-
| style="font-size: 85%; background: #F5F5F5;" colspan=2 |
:* 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
|-
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" colspan=2 | Table 5. Antifungal Prophylaxis in Patients with Cancer
|-
| style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" |
Disease/Therapy
: ALL
: AML
: MDS
: Autologous HSCT with mucositis
: Allogenic HSCT
: GVHD
| style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" |
Antifungal prophylaxis
: Fluconazole
: Posaconazole
: Posaconazole
: Fluconazole or micafungin
: Fluconazole or micafungin
: Posaconazole
|}
 
{{Seealso|NCCN Overall Infection Risk Categories}}
 
=== Low risk for infectious complications ===
Antimicrobial prophylaxis is not routinely recommended in these patients.  Antiviral agents may be considered in low risk patients with prior HSV episodes (Table 4).<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>
 
=== Intermediate risk for infectious complications ===
For the intermediate risk patients, antibacterial prophylaxis with fluoroquinolones should be considered.  Herpes simplex virus prophylaxis should be given during periods of neutropenia, and for autologous HSCT recipients, until at least 30 days following transplant.  Prophylaxis for varicella zoster virus should be maintained for at least 1 year after HSCT.  Antifungals may be considered during periods of neutropenia and for anticipated mucositis for intermediate risk patients.
 
=== High risk for infectious complications ===
For the high risk patients, antibacterial prophylaxis with fluoroquinolones should be considered.  Herpes simplex virus prophylaxis should be given during periods of neutropenia, and for autologous HSCT recipients, until at least 30 days following transplant.  Prophylaxis for varicella zoster virus should be maintained for at least 1 year after HSCT.  Antifungals may be considered during periods of neutropenia for ALL, AML/MDS, allogeneic HSCT recipients, or patients with significant GVHD receiving immunosuppressive therapy.  In addition, allogeneic HSCT recipients, patients with ALL, and patients treated with alemtuzumab are all at increased risk for infection with Pneumocystis jirovecii.
 
=== Antibacterial Prophylaxis ===
Levofloxacin (500-750 mg oral or IV daily) significantly reduce episodes of fever and the number of documented infections, particularly gram-negative bacillary infections, among high-risk patients with cancer expected to develop profound neutropenia >7 days in duration.  The NCCN Guidelines advise that fluoroquinolone prophylaxis (levofloxacin is preferred) be considered in patients with an expected duration of neutropenia (ANC <1000 cells/mm<sup>3</sup>) for more than 7 days.  This is in agreement with the recommendations of the IDSA guidelines for the use of antimicrobial agents in neutropenic patients with cancer.<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>  Among patients with neutropenia who are at lowe risk of infectious complications, the main benefit of antibacterial prophylaxis is a reduction in fever rather than in documented infections.
 
According to the NCCN guidelines, prophylaxis for pneumococcal infection with penicillin should be initiated 3 months after HSCT and be continued until at least 1 year following transplant regardless of prior administration of pneumococcal vaccines. Prophylaxis should be continued in patients with chronic GVHD until immunosuppressive therapy has been discontinued.
 
=== Antifungal Prophylaxis ===
The rationale for antifungal prophylaxis is to prevent fungal infections in a targeted group of high-risk patients (Table 5).<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>  Therapeutic drug monitoring (TDM) for the pharmacokinetic evaluation is generally recommended for patients receiving triazoles other than fluconazole. Currently, there is no sufficient evidence to support the use of TDM for the evaluation of polyenes or echinocandins.
 
=== Antiviral Prophylaxis ===
 
==== Herpes Simplex Virus ====
Herpes simplex virus (HSV) prophylaxis should be administered in patients with positive serology undergoing chemotherapy for acute leukemia during the period of neutropenia and in patients receiving hematopoietic stem cell transplantation (HSCT) for at least 30 days.  A longer duration of pre-emptive therapy may be considered in allogenic HSCT recipients with severe graft-versus-host disease.  For patients receiving alemtuzumab-containing regimens, HSV prophylaxis is advised until at least 2 months after completion of therapy or until CD4+ cell counts are 200 cells/mm<sup>3</sup> or more, whichever occurs later.<ref>{{Cite journal | issn = 1526-9655 | volume = 4 | issue = 4 | pages = 220–227 | last = Keating | first = Michael | coauthors = Stephen Coutré, Kanti Rai, Anders Osterborg, Stefan Faderl, Ben Kennedy, Tom Kipps, Gerald Bodey, John C. Byrd, Steven Rosen, Claire Dearden, Martin J. S. Dyer, Peter Hillmen | title = Management guidelines for use of alemtuzumab in B-cell chronic lymphocytic leukemia | journal = Clinical Lymphoma | date = 2004-03 | pmid = 15072613 }}</ref>  Prophylaxis against HSV may also be considered in patients with protracted neutropenia or patients receiving high-dose corticosteroids or fludarabine.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>  Acyclovir or valacyclovir is the initial drug of choice, whereas foscarnet is reserved for resistant strains.<ref>{{Cite journal | doi = 10.1093/cid/cir073 | issn = 1537-6591 | volume = 52 | issue = 4 | pages = –56-93 | 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 America | 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 = 21258094 }}</ref><ref>{{Cite journal | doi = 10.1038/bmt.2009.258 | issn = 1476-5365 | volume = 44 | issue = 8 | pages = 471–482 | last = Zaia | first = J. | coauthors = L. Baden, M. J. Boeckh, S. Chakrabarti, H. Einsele, P. Ljungman, G. B. McDonald, H. Hirsch, Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, European Blood and Marrow Transplant Group, American Society of Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Disease Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Diseases Canada, Centers for Disease Control and Prevention | title = Viral disease prevention after hematopoietic cell transplantation | journal = Bone Marrow Transplantation | date = 2009-10 | pmid = 19861981 }}</ref>
 
==== Varicella Zoster Virus ====
Herpes zoster occurs primarily in patients with defective cell-mediated immunity.  Varicella zoster virus (VZV) prophylaxis is advisable for seropositive patients for at least one year after allogenic or autologous HSCT and should be continued if immunosuppressive therapy is administered.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>  Patients undergoing therapy with T-cell–depleting agents such as alemtuzumab or fludarabine should also receive prophylaxis against VZV.  In addition, the use of proteasome inhibitors including carfilzomib and bortezomib is associated with a heightened risk for VZV reactivation.  Acyclovir, valacyclovir, or famciclovir is generally considered the agent of choice in these settings.<ref>{{Cite journal | doi = 10.1200/JCO.2007.14.9641 | issn = 1527-7755 | volume = 26 | issue = 29 | pages = 4784–4790 | last = Chanan-Khan | first = Asher | coauthors = Pieter Sonneveld, Michael W. Schuster, Edward A. Stadtmauer, Thierry Facon, Jean-Luc Harousseau, Dina Ben-Yehuda, Sagar Lonial, Hartmut Goldschmidt, Donna Reece, Rachel Neuwirth, Kenneth C. Anderson, Paul G. Richardson | title = Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study | journal = Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology | date = 2008-10-10 | pmid = 18711175 }}</ref><ref>{{Cite journal | doi = 10.1007/s00277-006-0227-9 | issn = 1432-0584 | volume = 86 | issue = 4 | pages = 301–302 | last = Varettoni | first = Marzia | coauthors = Camilla Vassallo, Giovanni Borroni, Silvia Mangiacavalli, Patrizia Zappasodi, Renato Rosso, Mario Lazzarino, Alessandro Corso | title = Late onset of bortezomib-associated cutaneous reaction following herpes zoster | journal = Annals of Hematology | date = 2007-04 | pmid = 17131123 }}</ref><ref>{{Cite journal | doi = 10.1200/JCO.2007.14.2372 | issn = 1527-7755 | volume = 26 | issue = 29 | pages = 4777–4783 | last = Reece | first = Donna E. | coauthors = Giovanni Piza Rodriguez, Christine Chen, Suzanne Trudel, Vishal Kukreti, Joseph Mikhael, Mariela Pantoja, Wei Xu, A. Keith Stewart | title = Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma | journal = Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology | date = 2008-10-10 | pmid = 18645194 }}</ref><ref>{{Cite journal | doi = 10.1002/ajh.20838 | issn = 0361-8609 | volume = 82 | issue = 5 | pages = 403–404 | last = Tong | first = Yin | coauthors = Jie Qian, Ying Li, Hai Meng, Jie Jin | title = The high incidence of varicella herpes zoster with the use of bortezomib in 10 patients | journal = American Journal of Hematology | date = 2007-05 | pmid = 17133426 }}</ref>
 
==== Cytomegalovirus ====
Cytomegalovirus (CMV) may occur as a primary infection in seronegative patients or result from reactivation in patients with positive serology.  Prevention of CMV disease after allogeneic HSCT can be accomplished with use of either prophylactic or preemptive therapy.  Prophylactic strategy entails the use of antiviral agents in all allogenic HSCT recipients if either the donor or recipient is seropositive for CMV.  Pre-emptive therapy involves active surveillance (i.e., detection of CMV DNA or p65 antigen in the peripheral circulation) and deployment of antiviral agents such as ganciclovir, foscarnet, or cidofovir.<ref>{{Cite journal | doi = 10.1038/sj.bmt.1700630 | issn = 0268-3369 | volume = 19 | issue = 2 | pages = 135–142 | last = Prentice | first = H. G. | coauthors = P. Kho | title = Clinical strategies for the management of cytomegalovirus infection }}</ref>  CMV surveillance is recommended in allogenic HSCT recipients for at least 6 months after transplantation and in chronic GVHD requiring immunosuppressive therapy and until the CD4+ count is 100 cells/mm<sup>3</sup> or more.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>  Patients receiving alemtuzumab therapy should undergo routine surveillance for CMV reactivation and weekly monitoring during therapy and at least 2 months after completion of treatment.  Upon confirmation of CMV antigenemia, pre-emptive therapy with valganciclovir, ganciclovir, foscarnet, or cidofovir should be administered for at least 2 weeks and until CMV is undetectable.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>
 
==== Hepatitis B Virus ====
High risk groups for hepatitis B virus (HBV) infection refer to patients with HBsAg+ serology or with prior resolved HBV infection (HBsAg-, HBsAb+, HBcAb+ serology) or with increasing HBV viral load planned for allogeneic HSCT, anti-CD20, or anti-CD52 monoclonal antibody therapy.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>  In HBsAg+ or HBcAb+ individuals, baseline quantitative PCR for HBV DNA should be obtained. In allogeneic HSCT candidates with active HBV infection, the transplant should be delayed and antiviral therapy should be administered for 3 to 6 months prior to conditioning.<ref>{{Cite journal | doi = 10.1038/bmt.2009.258 | issn = 1476-5365 | volume = 44 | issue = 8 | pages = 471–482 | last = Zaia | first = J. | coauthors = L. Baden, M. J. Boeckh, S. Chakrabarti, H. Einsele, P. Ljungman, G. B. McDonald, H. Hirsch, Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, European Blood and Marrow Transplant Group, American Society of Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Disease Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Diseases Canada, Centers for Disease Control and Prevention | title = Viral disease prevention after hematopoietic cell transplantation | journal = Bone Marrow Transplantation | date = 2009-10 | pmid = 19861981 }}</ref>  Candidates with no active HBV infection should undergo monitoring of HBV DNA with antiviral prophylaxis throughout HSCT procedure and at least 6 to 12 months after transplant.  Routine surveillance for HBV DNA and antiviral prophylaxis for at least 6 to 12 months following the last dose of therapy are recommended in HBsAg+ or HBcAb+ patients with hematologic malignancies receiving monoclonal antibodies such as rituximab, ofatumumab, or alemtuzumab.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref>  The choice of antiviral agents such as adefovir, entercavir, lamivudine, telbivudine, or tenofovir should be based upon efficacy, resistance, and safety profile.
 
=== Prophylaxis for ''Pneumocystis jirovecii'' ===
Antipneumocystis prophylaxis is recommended for allogenic HSCT recipients for at least 6 months and while receiving immunosuppressive therapy.  For patients with acute lymphocytic leukemia, prophylactic therapy should be continued throughout antileukemic therapy. Individuals undergoing alemtuzumab treatment should also receive prophylaxis against ''Pneumocystis jirovecii'' for a minimum of two months after the last dose and until CD4+ count is greater than 200 cells/mm<sup>3</sup>.<ref>{{Cite web | title =  Prevention and Treatment of Cancer-Related Infections | accessdate =  | url = http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf }}</ref> Trimethoprim/sulfamethoxazole (TMP/SMX) is considered as the treatment of choice; atovaquone, dapsone, or pentamidine may be used if the patient cannot tolerate TMP/SMX.  Prophylaxis is also advisable in patients receiving concomitant temozolomide and radiotherapy and should be continued until recovery from lymphopenia.<ref>{{Cite | title = TEMODAR | accessdate =  | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021029s026lbl.pdf }}</ref>
 
==== IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antibacterial Prophylaxis ====
{| 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.''' Levofloxacin and ciprofloxacin have been evaluated most comprehensively and are considered to be roughly equivalent, although levofloxacin is preferred in situations with increased risk for oral mucositis-related invasive viridans group streptococcal infection. A systematic strategy for monitoring the development of fluoroquinolone resistance among gram- negative bacilli is recommended. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''2.''' Addition of a gram-positive active agent to fluoroquinolone prophylaxis is generally not recommended. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''3.''' Antibacterial prophylaxis is not routinely recommended for low-risk patients who are anticipated to remain neutropenic for <7 days. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<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.''' Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC ≤100 cells/mm<sup>3</sup> for >7 days). ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|}
 
==== IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antifungal Prophylaxis ====
{| 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.''' Empirical antifungal therapy and investigation for invasive fungal infections should be considered for patients with persistent or recurrent fever after 4–7 days of antibiotics and whose overall duration of neutropenia is expected to be <7 days. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''2.''' In low-risk patients, the risk of invasive fungal infection is low, and therefore routine use of empirical antifungal therapy is not recommended. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''3.''' Prophylaxis against Candida infection is recommended in patient groups in whom the risk of invasive candidal infection is substantial, such as allogeneic hematopoietic stem cell transplant (HSCT) recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia. Fluconazole, itraconazole, voriconazole, posaconazole, micafungin, and caspofungin are all acceptable alternatives. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''4.''' Prophylaxis against Aspergillus infection in pre- engraftment allogeneic or autologous transplant recipients. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''5.''' Antifungal prophylaxis is not recommended for patients in whom the anticipated duration of neutropenia is <7 days. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|}
 
{| class="wikitable" style="width: 80%;"
|-
| colspan="1" style="text-align:center; background: LightCoral;" | [[IDSA guidelines classification scheme#Strength of Recommendations|Class C]]
|-
|bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' A mold-active agent is recommended in patients with anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HSCT. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<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.''' Data are insufficient to recommend a specific empirical antifungal agent for a patient already receiving anti- mold prophylaxis, but switching to a different class of anti- mold antifungal that is given intravenously should be considered. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' Preemptive antifungal management is acceptable as an alternative to empirical antifungal therapy in a subset of high- risk neutropenic patients. Those who remain febrile after 4–7 days of broad-spectrum antibiotics but are clinically stable, have no clinical or chest and sinus computed tomography (CT) signs of fungal infection, have negative serologic assay results for evidence of invasive fungal infection, and have no recovery of fungi (such as Candida or Aspergillus species) from any body site may have antifungal agents withheld. Antifungal therapy should be instituted if any of these indicators of possible invasive fungal infection are identified. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''3.''' Prophylaxis against invasive Aspergillus infections with posaconazole should be considered for selected patients >13 years of age who are undergoing intensive chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in whom the risk of invasive aspergillosis without prophylaxis is substantial. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|}
 
==== IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antiviral Prophylaxis ====
{| 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.''' Herpes simplex virus (HSV)–seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: I]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''2.''' Yearly influenza vaccination with inactivated vaccine is recommended for all patients being treated for cancer. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"| <nowiki>"</nowiki>'''3.''' Influenza virus infection should be treated with neuraminidase inhibitors if the infecting strain is susceptible. ''([[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: LightCoral;" | [[IDSA guidelines classification scheme#Strength of Recommendations|Class C]]
|-
|bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' Antiviral treatment for HSV or varicella-zoster virus (VZV) infection is only indicated if there is clinical or laboratory evidence of active viral disease. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LightCoral"|<nowiki>"</nowiki>'''2.''' In the setting of an influenza exposure or outbreak, neutropenic patients presenting with influenza-like illness should receive treatment empirically. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<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.''' Respiratory virus testing (including testing for influenza, parainfluenza, adenovirus, respiratory syncytial virus [RSV], and human metapneumovirus) and chest radiography are indicated for patients with upper respiratory symptoms (eg, coryza) and/or cough. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (>7 days after the last treatment) or >2 weeks before chemotherapy starts. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''3.''' Routine treatment of RSV infection in neutropenic patients with upper respiratory disease should not be given. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: III]])''<nowiki>"</nowiki>
|}
 
==== IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Adjunctive Therapy ====
{| 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.''' Prophylactic use of myeloid colony-stimulating factors (CSFs; also referred to as hematopoietic growth factors) should be considered for patients in whom the anticipated risk of fever and neutropenia is ≥20%. ''([[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.''' CSFs are not generally recommended for treatment of established fever and neutropenia. ''([[IDSA guidelines classification scheme#Quality of Evidence|Quality of Evidence: II]])''<nowiki>"</nowiki>
|}
 
==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>
* 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>


Line 544: Line 37:
* 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>
* 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>


== See Also ==
== References ==
*[[Neutropenia]]
{{reflist|2}}
 
== Related Chapters ==
*[[Chemotherapy]]
*[[Fever]]
*[[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]

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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

Overview

Historical Perspective

Pathophysiology

Causes

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria | Initial Assessment | History and Symptoms | Physical Examination | Laboratory Findings | CT | Other Diagnostic Studies

Treatment

Medical Therapy | Primary Prevention

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[1]
  • Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline[2]
  • 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[3]
  • Prevention and Treatment of Cancer-Related Infections: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology[4]
  • Management of Febrile Neutropenia: European Society for Medical Oncology Clinical Recommendations[5]

References

  1. ↑ Freifeld, Alison G. (2011-02-15). "Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America". Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 52 (4): 427–431. doi:10.1093/cid/ciq147. ISSN 1537-6591. PMID 21205990. Unknown parameter |coauthors= ignored (help)
  2. ↑ Flowers, Christopher R. (2013-02-20). "Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 31 (6): 794–810. doi:10.1200/JCO.2012.45.8661. ISSN 1527-7755. PMID 23319691. Unknown parameter |coauthors= ignored (help)
  3. ↑ Lehrnbecher, Thomas (2012-12-10). "Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 30 (35): 4427–4438. doi:10.1200/JCO.2012.42.7161. ISSN 1527-7755. PMID 22987086. Unknown parameter |coauthors= ignored (help)
  4. ↑ "Prevention and Treatment of Cancer-Related Infections" (PDF).
  5. ↑ Marti, F. Marti (2009-05). "Management of febrile neutropenia: ESMO clinical recommendations". Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 20 Suppl 4: 166–169. doi:10.1093/annonc/mdp163. ISSN 1569-8041. PMID 19454445. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)

Related Chapters

External Links

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