Documente Academic
Documente Profesional
Documente Cultură
net/publication/281728391
Febrile Neutropenia
CITATIONS READS
0 548
3 authors, including:
All content following this page was uploaded by Jeffery Auletta on 22 December 2015.
prophylaxis), and possible infectious exposures cific pathogens (i.e., respiratory viruses), prior
at home and school as well as recent travel history of fevers and documented infections,
(Orudjev and Lange 2002). Additional history and pathogen colonization (e.g., methicillin-
should focus on community outbreaks of spe- resistant Staphylococcus aureus [MRSA],
4 B.E. Gonzalez et al.
Table 1.2 Diagnostic evaluation based upon organ system involvement and physical findings
Organ system Physical findings Diagnostic evaluation based upon physical finding(s)
Head, ears, nose, Mucositis HSV, VZV, Enterovirus/Parechovirus PCR/DFA/viral
and throat Thrush culture (PCR preferred)
Oral lesions Biopsy unusual oral lesions (histology and
Pre-septal/orbital cellulitis microbiology)
Facial pain CT scan of the sinuses, orbits, temporal bones (obtain
Rhinorrhea sample)
Otorrhea Sinus drainage sample if able to perform and send for
bacterial, fungal, and viral culture
Nasopharyngeal secretions for respiratory viral
culture/antigen panel and PCR
Respiratory Cough/respiratory distress CT chest
Hypoxemia Legionella urine antigen
Chest radiograph infiltrates PCP evaluation: BAL, (1,3)-β-d-glucan, LDH
Sputum culture if able to perform
Aspergillus galactomannan, (1,3)-β-d-glucan
Histoplasma urine and serum antigen
Vascular access Exit site/tunnel erythema or discharge Blood culture from all ports (consider bacteria, fungus,
sites mycobacteria)
Gram stain and culture (bacteria, fungal) exit site
discharge
Gastrointestinal Diarrhea C. difficile PCR
Perirectal pain Viral stool culture/PCR (adenovirus, norovirus, etc.)
Abdominal pain SSYC and/or O&P if exposure by history
Ultrasound or CT abdomen/pelvis
Liver function test, amylase, lipase
Skin Rash DFA/PCR/viral culture of vesicular lesion
Cellulitis Dermatology evaluation and biopsy of cellulitis
or undiagnosed rash/lesion and send for culture
(bacterial, fungal, and atypical mycobacteria)
Musculoskeletal Arthritis Arthrocentesis: fluid for cell count and differential,
Limp/point tenderness cultures for bacteria, fungus, and mycobacteria
Lower back pain CT/MRI extremity or site
Urine culture (bacteria, fungal, consider adenovirus,
BK, CMV PCR)
Central nervous Change in mental status CT/MRI brain (consider MRA/V)
system Headache Lumbar puncture: cell count, bacterial and fungal stain
and culture, viral PCR (consider CMV, EBV,
Enterovirus, HHV-6, HSV, VZV)
HSV herpes simplex virus, VZV varicella zoster virus, DFA direct fluorescence antibody, CT computed tomography,
PCR polymerase chain reaction, PCP Pneumocystis jiroveci (carinii) pneumonia, BAL bronchoalveolar lavage, LDH
lactate dehydrogenase, SSYC Salmonella, Shigella, Yersinia, Campylobacter, O&P ova and parasites, MRI magnetic
resonance imaging, CMV cytomegalovirus, MRA/V magnetic resonance arterio/venogram, EBV Epstein-Barr virus,
HHV-6 human herpesvirus-6
vancomycin-resistant Enterococcus [VRE]). access sites), but rather on all sites of common
A comprehensive review of each organ system childhood infection such as the ears, throat, and
is important to determine possible etiologies of skin (Auletta et al. 1999). Information obtained
the fever. The physical exam should be thor- from the review of systems and physical find-
ough and not focus only on common sites of ings will direct laboratory and ancillary evalua-
infection unique to the febrile neutropenic child tions and influence the choice of antimicrobial
(i.e., oral and perirectal mucosa, central venous therapy.
1 Febrile Neutropenia 5
1.3 Defining the Risk for Serious Lehrnbecher et al. 2012). With the lack of sig-
Infection nificant randomized prospective data, Härtel
et al. (2007) strongly recommend against outpa-
Risk stratification for serious infection incorpo- tient management of FN in pediatric patients
rates the following variables: presenting clinical outside of clinical trials. In the recent pediatric
signs and symptoms, underlying cancer diag- FN expert consensus guidelines, Lehrnbecher
nosis and remission status, type of antitumor et al. (2012) recommend the use of local popu-
therapy received, and medical comorbidities lation-based stratification systems with careful
(Orudjev and Lange 2002; Paganini et al. 2007; prospective and continuous evaluation to ensure
Freifeld et al. 2011). Sepsis signs and symp- safety and efficacy.
toms, presence of a central venous access device In particular risk stratification schemata,
(CVAD), mucositis, infant acute lymphoblastic initial laboratory values such as platelet count
leukemia (ALL), acute myelogenous leukemia <50 × 109/L and C-reactive protein (CRP)
(AML), induction or intensification chemo- ≥90 mg/L have been noted to increase risk,
therapy, and leukemia in relapse have all been while absolute monocytosis ≥0.1–0.155 × 109/L
shown to increase infection-related morbidity (depending on study) has tempered risk (Rackoff
and mortality in pediatric patients and should be et al. 1996; Baorto et al. 2001; Santolaya et al.
regarded as high-risk features at initial FN pre- 2002; Ammann et al. 2010). Multiple labora-
sentation (Orudjev and Lange 2002; Wicki et al. tory assessments including CRP, procalcitonin,
2008; Badiei et al. 2011). Social factors including IL-6, and IL-8 have all been studied in pediatric
history of noncompliance and distance >1 h from and adult oncology patients to potentially define
clinical facility must be considered high-risk high-risk patients but none has been uniformly
conditions (Orudjev and Lange 2002; Paganini shown as an effective marker (Santolaya et al.
et al. 2007). Paganini et al. (2007) showed that 1994; Lehrnbecher et al. 1999; Uys et al. 2007;
advanced disease stage, bacteremia, and associ- Semeraro et al. 2010; Phillips et al. 2012). These
ated comorbities including persistent bleeding, studies have been recently reviewed by Phillips
refractory hypoglycemia, hypotension, altered et al. (2012).
mental status, renal insufficiency and hepatic
dysfunction were independent risk factors for
mortality. 1.4 Diagnostic Evaluation
The Multinational Association for Supportive
Care in Cancer (MASCC) risk index has been 1.4.1 Initial Laboratory Evaluation
prospectively validated in adults allowing for
potential outpatient management of low-risk The diagnostic evaluation for the pediatric patient
patients (Klastersky et al. 2000; Uys et al. 2004). with FN should be guided by clinical history and
Multiple risk prediction models for pediatric physical findings to optimize detecting an etiol-
oncology patients have been presented in the lit- ogy for the fever. Initial work-up includes a com-
erature and are reviewed by Orudjev and Lange plete blood cell count (CBC), a comprehensive
(2002), Härtel et al. (2007), Phillips et al. metabolic panel, and blood cultures from each
(2010), and Lehrnbecher et al. (2012). No one port of a central catheter. The CBC will demon-
system has been found superior, none have strate the degree of neutropenia and monocytope-
undergone rigorous prospective validation to nia, and the metabolic panel will evaluate renal
ensure patient safety across populations, and no and hepatic function, which could be affected by
prospectively validated stratification for high- previous chemotherapeutic agents and may influ-
risk patients has been identified (Härtel et al. ence antimicrobial selection and dosing. For
2007; te Poele et al. 2009; Phillips et al. 2010; example, if the patient’s creatinine is elevated,
6 B.E. Gonzalez et al.
as CT-guided biopsy of lung lesions for histo- to support the use of this modality as first-line
logic and microbiologic assessment. Importantly, imaging in pediatrics given its inherent expense
radiologic findings of common molds in children and associated radiation exposure (Xu et al.
may differ from those in adults. For example, 2010; Haroon et al. 2012).
pulmonary nodules are common findings in
pediatric patients with Aspergillus, while the
halo and crescent signs occur less frequently 1.4.3 Biomarkers for Invasive
than in adult patients (Thomas et al. 2003; Fungal Infection (IFI)
Burgos et al. 2008). Therefore, consultation with
pediatric radiologists is critical when interpret- Early identification of infection in FN, especially
ing these studies. Providing the radiologist with IFI, critically affects patient survival. Biomarkers
information about the patient’s clinical presenta- for IFI have proven useful in the adult population
tion, level of neutropenia, and current support- as adjuncts to clinical findings and imaging.
ive therapy including specific antimicrobial and Limited pediatric data suggest these biomarkers
growth factor use increases the diagnostic utility may also be used in children with similar sensi-
of CT (Heussel 2011). tivities and specificities as defined in adults.
1.4.3.2 (1,3)-β-D-glucan (BDG) limited its current use and more data are required
Serum BDG, an important cell-wall component to make firm recommendations.
of most fungi including Pneumocystis jiroveci
(former carinii), has been measured in adult
patients with IFI and hematologic malignancies 1.4.4 Viral Studies
(Marty and Koo 2009). Like GMN, studies using
serum BDG in the pediatric population are lim- Viral infections may cause prolonged fevers in
ited. In fact, few studies performed to date even neutropenic patients. Seasonal viral infections
establish a normal value for children, which may such as influenza A/B and respiratory syncytial
be higher than the 60 pg/mL cutoff used in adult virus (RSV) in the winter and enterovirus in the
patients (Smith et al. 2007; Mularoni et al. 2010). summer must be considered (Lindblom et al.
In immunocompromised adult patients, serum 2010; Ozdemir et al. 2011). In patients with
BDG levels exceeding 500 pg/mL have been used mucositis, herpes simplex virus (HSV) should be
to diagnose P. jiroveci (Del Bono et al. 2009; Koo considered. Viral PCR (whole blood and plasma,
et al. 2009; te Poele et al. 2009). One pediatric cerebrospinal fluid, stool) is commercially
study found serum BDG potentially useful for available and enables faster identification of viral
P. jiroveci diagnosis in three patients with hema- etiologies at higher sensitivity and specificity
tologic malignancies, one with BAL fluid confir- compared to viral culture. In addition, direct
mation (Gonzalez et al. 2011). The sensitivity of fluorescent antibody (DFA) testing of cutaneous
BAL for diagnosing P. jiroveci pneumonia is lesions may expedite diagnosis of herpetic skin
lower in non-HIV patients and in patients receiv- infections (i.e., HSV, varicella).
ing aerosolized pentamidine. Therefore, serum
BDG may be a useful adjunctive, noninvasive
diagnostic tool (Levine et al. 1992; Azoulay and 1.4.5 Invasive Procedures:
Schlemmer 2006; Jiancheng et al. 2009). More Bronchoalveolar Lavage
pediatric studies are needed to define serum BDG (BAL) and Tissue Biopsy
as a reliable indicator of IFI such as P. jiroveci.
Serum BDG does not detect Cryptococcus Tissue is necessary for diagnosis when physi-
or Zygomycetes spp. (e.g., Mucor, Rhizopus, cal examination or radiographic imaging is con-
Absidia), which do not produce BDG. False posi- cerning for abscess formation or lesions of the
tives also occur in patients receiving antimicro- skin, sinuses, or organ parenchyma but with-
bial agents such as piperacillin/tazobactam in out corroborative microbiologic confirmation.
addition to hemodialysis with cellulose mem- Microbiologic evaluations should include proper
branes, intravenous albumin and immunoglobulin sample collection for assessing AFB and other
(Marty and Koo 2009; Karageorgopoulos et al. bacterial and fungal pathogens. For IFI such as
2011). Finally, the test may serve as a prognostic chronic disseminated candidiasis or invasive
marker for invasive candidiasis when serial levels Aspergillus spp., hepatic or splenic biopsy may
are measured, but data supporting this indication be required (Masood and Sallah 2005).
are limited (Ginocchio et al. 2012; Glotzbecker In children with pulmonary lesions, BAL
et al. 2012; Jaijakul et al. 2012). should be attempted first as it has a low complica-
tion rate and may yield an etiologic agent
1.4.3.3 Polymerase Chain (Pattishall et al. 1988; Jain et al. 2004; Efrati
Reaction (PCR) et al. 2007). CT-guided lung biopsy or wedge
Molecular methodology such as PCR testing resection may be necessary if BAL sampling is
may improve the detection of IFI as well as bac- nondiagnostic in the patient with persistent fever
terial or viral organisms in children with FN and pulmonary nodules (Wingard et al. 2012). In
(Santolaya et al. 2011; Kourkoumpetis et al. addition to routine cultures, BAL samples should
2012). However, lack of standardization has be analyzed by GMN assay (Wingard et al. 2012).
1 Febrile Neutropenia 9
In patients with neutropenia, skin lesions may has also published guidelines for FN in pediatric
be a manifestation of localized or systemic infec- oncology patients (Lehrnbecher et al. 2012).
tion (Mays et al. 2006). Ecthyma gangrenosum, a Recommendations from such practice guidelines
black eschar with surrounding erythema origi- are mostly based upon level III evidence (expert
nally attributed to Pseudomonas spp., can be opinion) versus level I and II evidence (results
caused by many other bacterial as well as fungal from randomized clinical trials) (Lee and
and viral pathogens (Moyer et al. 1977; Reich Vielemeyer 2011). Furthermore, no formal guide-
et al. 2004; Son et al. 2009). Many invasive lines for FN have been published by the American
systemic fungal infections with high potential for Society of Pediatric Hematology/Oncology
dissemination like Zygomycetes spp., Aspergillus (ASPHO) or the Pediatric Infectious Diseases
spp. and Candida spp. may present as nonspe- Society (PIDS) despite notable disparity among
cific lesions that require prompt evaluation (Mays adult and pediatric cancer patients, including dif-
et al. 2006). Contaminated medical equipment ferences in underlying malignant diseases and
such as adhesive tape has been associated with associated therapies, immunity and susceptibility
nosocomial outbreaks of Zygomycetes spp., so it to pathogens, and antimicrobial pharmacodynam-
is imperative to consider such infections in skin ics (PD) and pharmacokinetics (PK) (Sung et al.
lesions found under dressings near tape (Everett 2011; Watt et al. 2011). Defining such PD/PK dif-
et al. 1979; Lalayanni et al. 2012). Prompt punch ferences are critical, particularly in the cancer
biopsy and consideration for consultation with a patient as cancer therapy can affect antimicrobial
dermatology specialist is advisable. efficacy, promoting pathogen resistance
(Theuretzbacher 2012). Whether such differences
significantly impact infection-related morbidity
1.5 Empiric Management and mortality in pediatric cancer patients remains
of Febrile Neutropenia (FN) largely unstudied.
The International Antimicrobial Therapy
Management of FN in pediatric oncology is often Cooperative Group (IATCG) published the largest
based on institutional and consensus guidelines. To series comparing FN episodes in adult (n = 2,321)
inform decision-making we review the appropriate and pediatric (n = 759) patients receiving stan-
literature regarding specific topics including the use dardized disease assessment and empiric therapy
of monotherapy versus combination antibiotic ther- and noted significant differences in patient demo-
apy, use of vancomycin, empiric utilization of anti- graphics and outcomes by age: (1) malignant
fungals, emergence of resistant pathogens, duration diagnoses associated with FN episodes differed
and location of therapy, and criteria for central across patient age with ALL being most frequent
venous catheter removal. Pediatric FN guidelines in children and AML most frequent in adults;
from one institution are provided as an example of (2) adult patients more frequently received anti-
how these concepts can be practically implemented. bacterial and antifungal prophylaxes; (3) children
tended to have lower ANCs at presentation but
shorter durations of granulocytopenia; (4) children
1.5.1 Adult FN Guidelines had less defined sites of infection and more fever
for Empiric Therapy: of unknown origin; (5) children and adults had
Do They Apply to Children? similar rates of Gram-positive and Gram-negative
bacteremia, but children had more streptococcal
Infectious Diseases Society of America (IDSA) bacteremia; and (6) children had lower infection-
guidelines for empiric antimicrobial therapy for related mortality and overall mortality (3 % vs.
FN patients serve as the foundation for institu- 10 %) than adult FN patients (Hann et al. 1997).
tional protocols treating pediatric cancer patients Together, these data suggest that children and
(Freifeld et al. 2011). Notably, the International adults with FN are indeed distinct both in presen-
Pediatric Fever and Neutropenia Guideline Panel tation and outcome.
10 B.E. Gonzalez et al.
Additional studies are needed to investigate microbial patterns and specific antimicrobial
further these suggestive data. However, such clin- therapies.
ical investigation is practically limited by the large
numbers of patients required for accurate statisti- 1.5.2.1 Monotherapy Versus
cal analysis as well as by the inherent expense Combination Therapy
associated with large randomized clinical trials Pizzo et al. (1986) first showed that cephalos-
(RCTs) (Mullen 2012). Likewise, reproducible porin monotherapy is as effective as combination
and accurate biomarkers of response to infection therapy in adult oncology patients. Since that time,
and clinical end points are needed to ensure sound institutional guidelines are slowly adopting the
clinical trials addressing antimicrobial efficacy recommendation for monotherapy that is supported
and safety (Powers 2012). Given their limitations in both the IDSA as well as the recent pediatric
in study design and expense, RCTs comparing FN guidelines (Freifeld et al. 2011; Lehrnbecher
episodes and response to therapy among adult and et al. 2012). In a Cochrane review of 71 pub-
pediatric cancer patients will likely not be per- lished trials, monotherapy with broad-spectrum,
formed. Yet, extensive pediatric literature incor- antipseudomonal beta-lactams was found to be
porating antimicrobial agents used in adult FN non-inferior to combination therapy with a trend
demonstrates that empiric antibacterial and anti- toward improved survival and a significantly
fungal therapies are comparable in their efficacy. decreased risk of adverse events, specifically fun-
For these reasons, extrapolation of adult FN guide- gal infection and nephrotoxicity secondary to
lines to the pediatric population is unavoidable. aminoglycosides as part of combination therapy
(Paul et al. 2013). The observations of Paul et al.
(2013) have been corroborated by a previous sys-
1.5.2 Choice of Empiric tematic meta-analysis by Furno et al. (2002).
Antimicrobial Therapy Specifically for pediatric oncology patients,
Manji et al. (2012b) conducted a meta-analysis
As discussed, determination of initial risk stratifi- and found no significant difference between
cation can help guide utilization of appropriate antipseudomonal penicillins and antipseudo-
antimicrobial agents and specifically the route (oral monal cephalosporins either as monotherapy or
vs. intravenous), setting (inpatient vs. outpatient), when combined with an aminoglycoside. The
and duration of use. In general, antimicrobial authors therefore recommend choosing a regi-
choices for empiric pediatric FN are comparable men based on cost, availability and local factors
in their efficacy in either high-risk or low-risk such as institutional resistance patterns. Whether
scenarios as serious medical complications remain the increased utilization of a more broad-spec-
low with use of contemporary treatments (Baorto trum agent as monotherapy over a more narrow-
et al. 2001; Luthi et al. 2012; Manji et al. spectrum antipseudomonal cephalosporin plus an
2012b, c). Therefore, institutional guidelines for aminoglycoside will lead to increased resistance
empiric antimicrobial therapy should consider the for these agents is unknown.
following: (1) published experience with using In an additional Cochrane review of anti-
the antimicrobial agent in the context of FN; (2) Gram-positive antibiotics (often vancomycin) in
physician experience with using the proposed FN, Paul et al. (2005) showed that the addition of
antimicrobial agent; (3) pathogen epidemiology such therapy does not improve outcomes without
and resistance patterns to the antimicrobial agent a documented Gram-positive infection. Use of
inherent to the institution and its surrounding vancomycin as initial empiric FN therapy is not
community; and (4) the antimicrobial agent’s tox- recommended in consensus guidelines as it does
icity profile, cost and availability. In essence, not significantly affect survival or length of stay
choice of empiric antimicrobial therapy should (Freifeld et al. 2011; Lehrnbecher et al. 2012).
integrate the patient’s clinical history and pre- Furthermore, imprudent use of vancomycin has
sentation with institutional experience of local been associated with emergence of resistant
1 Febrile Neutropenia 11
pathogens (e.g., VRE) and nephrotoxicity. et al. 2012). Ceftazidime is not a good first-line
Clinical indications for empiric vancomycin choice for monotherapy due to reduced Gram-
include skin/soft-tissue and catheter-related positive coverage as well as induction of
infection, hemodynamic instability, severe β-lactamase production leading to subsequent
mucositis, and pneumonia. In these situations, emergence of resistant pathogens and inferior
targeted vancomycin trough levels and renal clinical outcomes in pediatric patients (Mebis
function surveillance are recommended (Rybak et al. 1998; Ariffin et al. 2000; Greenberg et al.
et al. 2009). If susceptible bacteria are not recov- 2005). Paul et al. (2010) additionally noted that
ered or if concern for Gram-positive infection carbapenem monotherapy had similar all-cause
abates, vancomycin should be discontinued mortality as other monotherapy regimens but
within 72 h (Lehrnbecher et al. 2012). was associated with higher rates of antibiotic-
Consensus guidelines recommend combination and Clostridium difficile-associated diarrhea.
therapy be reserved for specific clinical indications Pediatric meta-analyses have shown similar
including patient instability, concern for resistant effectiveness between antipseudomonal cepha-
pathogens (e.g., extended spectrum β-lactamase losporins, antipseudomonal penicillins and car-
[ESBL]-producing Serratia , Pseudomonas, bapenems as monotherapy but without the noted
Acinetobacter, Citrobacter, Enterobacter and increase in Clostridium difficile-associated diar-
Klebsiella spp.), and need for synergism to rhea (Manji et al. 2012b, c).
treat specific pathogens (e.g., Enterococcus,
Mycobacterium spp., MRSA) or infections (e.g., 1.5.2.3 Alterations in Initial Empiric FN
endocarditis, cryptococcal meningitis) (Freifeld Antibiotic Management
et al. 2011; Lehrnbecher et al. 2012). Of note, if Once empiric therapy has been initiated, altera-
combination therapy is required, meta-analyses tions in FN antibiotic management may be
in pediatrics recommend utilization of once required to optimize treatment; these changes
rather than multiple daily doses of aminoglyco- occur at the discretion of the practitioner or
sides due to trends toward improved efficacy and institution without significant evidence basis.
decreased nephrotoxicity (Sung et al. 2003; For instance, Lehrnbecher et al. (2012) recom-
Contopoulos-Ioannidis et al. 2004). mend discontinuing combination therapy (if
initiated at presentation) after 24–72 h in the
1.5.2.2 Which Monotherapy to Choose stable patient without microbiologic evidence
A Cochrane review of antipseudomonal beta- to continue both agents. Similarly, patients
lactams for initial management of FN compared who are stable but with persistent fever should
studies with ceftazidime, cefepime, piperacillin/ not have their initial regimen escalated. Those
tazobactam, meropenem and imipenem (Paul who become unstable should have additional
et al. 2010). Cefepime monotherapy was shown coverage for potential resistant Gram-negative,
to have a significantly higher all-cause mortality Gram-positive and anaerobic causes initi-
which had been previously reported (Yahav ated with consideration for fungal and viral
et al. 2007). The Cochrane meta-analysis etiologies.
reported a nonsignificant higher rate of bacterial
superinfection with cefepime which has been a 1.5.2.4 Outpatient Management of FN
reported concern due to its limited anaerobic Although there remains a lack of one uniform
profile and poor coverage for skin infections pediatric oncology risk stratification system,
(Yahav et al. 2007; Paul et al. 2010; Kalil 2011). many institutions have begun to utilize outpa-
A follow-up meta-analysis did not find a statisti- tient management of low-risk FN which can
cally significant increased mortality with include outpatient oral or parenteral therapy as
cefepime and current pediatric consensus guide- either initial management or as step-down to
lines consider cefepime a reasonable choice for outpatient treatment after initial inpatient man-
monotherapy (Kim et al. 2010; Lehrnbecher agement; such options and the evidence
12 B.E. Gonzalez et al.
surrounding them are reviewed by Chisholm efficacy but lack of power to prove non-inferi-
and Dommett (2006). This differs from previ- ority for safety.
ous studies in which low-risk patients were Many centers are continuing to initially admit
discharged early (ANC <0.5 × 10 9/L) but only all pediatric oncology FN patients with the poten-
after defervescence (Mullen and Buchanan tial for early discharge with or without continued
1990; Aquino et al. 1997; Wacker et al. 1997). antibiotic support depending on the clinical con-
Meta-analyses of efficacy and safety from adult text (Gibson et al. 2013). The United Kingdom
and pediatric studies found no significant dif- recommends such a management strategy after
ference in treatment failure in the inpatient ver- 48 inpatient hours in patients >1 year of age,
sus outpatient setting and no significant without medical or social comorbidities, not
difference in the efficacy of outpatient oral ver- receiving extremely intensive therapy, appearing
sus parenteral therapy in low-risk FN (Teuffel clinically well without a source of infection, with
et al. 2011b). Studies were extremely heterog- some marrow recovery (i.e., ANC >0.1 × 109/L),
enous in terms of choice of antibiotics (both and with fever improvement (but not full defer-
oral and parenteral) as well as timing of step- vescence necessary), for outpatient oral antibiotics
down making generalizations difficult. A recent to complete a 5-day course (Gibson et al. 2013).
Cochrane review of randomized controlled tri- A recent survey of Canadian pediatric oncology
als comparing oral versus intravenous anti- centers found heterogenous treatment strategies
biotic therapy for FN found no significant from full inpatient care, to step-down care, to full
difference in treatment failure or mortality outpatient care exemplifying the perceived lack
(Vidal et al. 2013). of sufficient data to uniformly modify practice
The utilization of outpatient oral therapy (Boragina et al. 2007). Sung et al. (2004) reported
specifically for pediatric patients either at FN in a survey of parents that only 53 % supported
presentation or as step-down after initial inpa- initial FN outpatient management (as compared to
tient management was most recently reviewed 71 % of practitioners) due to perceived increased
by Manji et al. (2012a). Sixteen prospective tri- fear and anxiety balanced with increased comfort,
als were reviewed in the meta-analysis with no while early discharge and outpatient intravenous
significant difference between oral and paren- management are reportedly associated with
teral regimens and no outpatient infection- improved health-related quality of life (Cheng
related mortality. None of the trials were et al. 2011). Finally, Teuffel et al. (2011a) cal-
randomized controlled trials specifically com- culated that the most cost-effective model is one
paring inpatient versus outpatient management in which low-risk FN patients are treated entirely
and outcomes of low-risk FN (Manji et al. at home but through a parenteral rather than oral
2012a). The types of oral agents utilized in route. The risk of nosocomial infection (NI)
pediatric studies are quite heterogenous and with inpatient management must also be consid-
include amoxicillin/clavulanate, cefixime, fluo- ered and was reported to be 5.2 NI per 100
roquinolones (ciprofloxacin, gatifloxacin) and admissions by one group (Simon et al. 2000).
combination therapy (ciprofloxacin plus amoxi- The recent pediatric FN expert consensus guide-
cillin) (Mullen et al. 1999; Aquino et al. 2000; lines allow for consideration of initial or step-
Paganini et al. 2000, 2001; Shenep et al. 2001; down outpatient management for the low-risk
Park et al. 2003; Petrilli et al. 2007; Dommett patient in the appropriate setting although as a
et al. 2009; Brack et al. 2012). Ciprofloxacin weak recommendation (Lehrnbecher et al. 2012).
plus amoxicillin/clavulanate is recommended
as the oral regimen of choice in adult patients 1.5.2.5 Choice of Empiric Antifungal
(Freifeld et al. 2011). Brack et al. (2012) Therapy
recently reported on an RCT comparing contin- The use of empiric antifungal therapy in neutro-
ued inpatient treatment versus oral outpatient penic children is also based upon limited data
management and found non-inferiority for (Pizzo et al. 1982). Despite the low incidence of
1 Febrile Neutropenia 13
IFI in pediatric FN, cost of associated antifungal antifungal therapy in high-risk patients with
therapy and supportive care and IFI-related mor- persistent FN without a source while receiving
tality are high (Zaoutis et al. 2006; Kim et al. broad-spectrum antibiotics for ≥4 days (Freifeld
2011; Mor et al. 2011; Steinbach 2011). et al. 2011; Lehrnbecher et al. 2012). Pediatric
Therefore, recent emphasis has been placed on guidelines recommend either liposomal ampho-
defining risk factors for IFI and providing empiric tericin B or caspofungin while the adult IDSA
antifungal therapy only to high-risk FN patients guidelines admit there is insufficient evidence
(Cordonnier et al. 2009; Caselli et al. 2012; to recommend any one particular agent beyond
Lehrnbecher et al. 2012). Notable risk factors for ensuring for anti-mold coverage (Freifeld
IFI include hematologic malignancy, especially et al. 2011; Lehrnbecher et al. 2012; Groll
AML and relapsed disease, prolonged and pro- et al. 2014). Due to unclear efficacy of empiric
found neutropenia and lymphopenia, and adoles- antifungal prophylaxis in the prevention of IFI,
cent age (Groll et al. 1999; Rosen et al. 2005; the IDSA guidelines also suggest consideration
Castagnola et al. 2006; Mor et al. 2011). for “preemptive antifungal management” (i.e.,
The number of antifungals has increased withholding empiric therapy) as an alternative
dramatically over the last decade but efficacy strategy in patients who remain febrile >4 days
data in prevention of IFI in pediatric oncology but are clinically stable and have no clinical,
are very limited (Blyth 2011; Steinbach 2011). radiographic (CT sinus and chest), laboratory
Meta-analyses on the utilization of empiric (negative fungal serology screens), or microbio-
antifungal therapy has shown mixed benefit in logic (positive culture from sterile site) evidence
decreasing all-cause mortality (Gøtzsche and of fungal infection (Freifeld et al. 2011).
Johansen 2002; Goldberg et al. 2008). Similarly,
one small prospective pediatric study showed no
benefit with antimycotic prophylaxis as com- 1.5.3 Duration of Antimicrobial
pared to early therapeutic treatment (Uhlenbrock Therapy: Empiric Versus
et al. 2001). Additional meta-analyses of lim- Therapeutic Intent
ited trial data mainly from adult oncology
patients have shown that intravenous liposomal In the absence of documented or clinical concern
amphotericin B and potentially caspofungin for infection, empiric antimicrobial therapy is
(2 trials) are the most effective empiric agents often continued until resolution of FN in both
(Johansen and Gøtzsche 2000; Jørgensen et al. low- and high-risk patients. As mentioned, in
2006; Goldberg et al. 2008). Voriconazole was low-risk pediatric patients, discontinuing antibi-
reported to be non-inferior to liposomal ampho- otics prior to attaining an ANC >0.5 × 109/L has
tericin B as empiric antifungal therapy by Walsh been shown safe if afebrile ≥24 h and with nega-
et al. (2002), but this was refuted by a subse- tive cultures ≥48 h (Mullen and Buchanan 1990;
quent Cochrane review and not approved by the Aquino et al. 1997; Wacker et al. 1997;
US Food and Drug Administration (FDA) for Lehrnbecher et al. 2002; Hodgson-Viden et al.
this indication (Jørgensen et al. 2006). Clinical 2005; Lehrnbecher et al. 2012). Risk stratifica-
trials incorporating empiric antifungal therapy tion in these studies was heterogenous with no set
in pediatric FN are extremely limited. Maertens ANC threshold for early discharge; therefore,
et al. (2010) report that liposomal amphoteri- consensus pediatric guidelines recommend evi-
cin B and caspofungin are comparable in their dence of bone marrow recovery (i.e., post nadir
efficacy and safety although patient numbers ANC ≥0.1 × 109/L) prior to antimicrobial discon-
were small and it is unclear if the study was tinuation (Lehrnbecher et al. 2012). Santolaya
powered to make this conclusion (Sekine et al. et al. (1997) have also shown in a small low-risk
2010). Generalizability in regard to the efficacy carefully selected pediatric cohort that antimicro-
of other echinocandins is unknown. Consensus bials can be discontinued on day 3 of hospital
guidelines recommend initiation of empiric admission prior to defervescence or neutrophil
14 B.E. Gonzalez et al.
recovery; thus, consensus guidelines suggest dis- 2012). The interested reader is directed to
continuation of antimicrobials after 72 h of intra- recently published IDSA guidelines for a more
venous antibiotic therapy in the patient who is extensive discussion of infections due to
afebrile ≥24 h even without evidence of bone Aspergillus, Candida and Cryptococcus (Walsh
marrow recovery as long as close follow-up is et al. 2008; Pappas et al. 2009; Perfect et al.
ensured (Lehrnbecher et al. 2012). Again, the 2010).
data to support this practice comes from small
prospective trials with no uniform risk strati-
fication system. In high-risk patients, empiric 1.5.4 Endovascular Sources
antifungal therapy is usually discontinued once of Infection: Catheter
fever has resolved for ≥48 h with an ANC Removal
>0.5 × 109/L. If the patient remains afebrile and
clinically stable, antibiotic therapies are discon- Any central venous access device (CVAD)
tinued. Although definitive evidence is lacking, can cause central line-associated bloodstream
the usual clinical practice is to remove one anti- infection (CLABSI), including a peripherally
microbial agent per 24 h time interval to observe inserted central catheter (PICC) (Advani et al.
for fever recrudescence if the patient is on combi- 2011). As mentioned, although DTP between
nation antimicrobial therapy. No pediatric studies peripheral and central cultures can allow for
address the appropriate management strategy in determination of line infection versus bacte-
high-risk pediatric FN patients and specific man- remia, such information rarely changes man-
agement of these patients is not addressed in the agement. Rather, CVAD removal is necessary
pediatric consensus guidelines (Lehrnbecher in the following clinical contexts: any blood-
et al. 2012). stream infection in which the CVAD is no lon-
For documented infection, duration of ther- ger required, tunneled catheter site infection,
apy is determined by the site, pathogen and clin- hemodynamic instability/sepsis, endocarditis
ical response to therapy. Most bacterial or other endovascular infection (e.g., throm-
infections (with notable exceptions including bophlebitis), persistent positive blood culture
CNS infection, abscess formation and endovas- despite appropriate antimicrobial therapy for
cular focus) require 10–14 days of appropriate >72 h, and CLABSI due to highly resistant
therapy, assuming complete clinical and micro- pathogens (e.g., MRSA, ESBL Gram-negative
biologic response. In general, duration of anti- bacilli, VRE) or pathogens that are difficult to
microbial therapy should be continued through eradicate, particularly due to adhesive biofilm
a time of neutrophil recovery (i.e., at least 5 production (e.g., fungi, Propionibacterium spp.,
days beyond ANC >0.5 × 109/L), although there Bacillus spp. Mycobacterium spp.) (Mermel
is little evidence to support the efficacy of this et al. 2009). Delay in catheter removal for less
practice. For established IFI, prolonged therapy virulent pathogens increases the risk for recur-
(4–6 weeks) is necessary and concomitant rent CLABSI (Raad et al. 2009). Antibiotic
immune recovery is critical for favorable out- lock therapy, instilling high concentrations of
comes (Nucci et al. 2003). The role for combi- susceptible antibiotic or ethanol into the CVAD
nation antifungal therapy, particularly in the lumen, has been successfully used in combina-
context of mold infection, requires further tion with systemic antimicrobial therapy to both
investigation; potential utilization of combina- eradicate and prevent CLABSI and should be
tion therapy must balance the significant drug considered when the CVAD cannot be removed
interactions and potential side effects with ques- (e.g., limited access sites in the patient) (Fortun
tionable benefit (Vazquez 2008; Spellberg et al. et al. 2006; Flynn 2009).
1 Febrile Neutropenia 15
• Access central venous access device (CVAD); If unable or none present, place peripheral IV & obtain culture
• Obtain T&S, CBC with differential, renal and hepatic function, blood cultures from all lumens
• Obtain urinalysis and urine culture (but do not delay antibiotic admininstration)
• CXR, stool cultures, respiratory viral PCR panel if symptoms exist
• Order appropriate antibiotics (see below)
ANTIBIOTICS GIVEN WITHIN 1 HOUR OF ARRIVAL TO EMERGENCY ROOM
• Contact oncology service after assessment
Antimicrobial allergies:
Penicillin allergy:
• Cefepime + Metronidazole OR
• Assess risk‡ Admit • Meropenem
• Observe 1h post-ceftriaxone Assess Risk‡ Cephalosporin allergy:
• Discharge if clinically well • Meropenem
• Return to clinic next day if β-lactam allergy:
remains febrile, sooner if new • Fluoroquinolone
symptoms Vancomycin allergy:
Low Risk High Risk • Daptomycin (if no pulmonary
infection) OR
• Linezolid
‡Risk †Vancomycin
assessment criteria criteria
Patient is considered High Risk if ANY • Skin infection/cellulitis
of the following is present: • CVAD site infection
• Signs/symptoms of sepsis • Mucositis
• ANC < 0.1 x 109/L • AML or recent high-dose cytarabine administration
• Focal infection (e.g. mucositis, abdominal • Isolation of vancomycin-sensitive organism
pain, perianal tenderness) • Previous MRSA or Streptococcus viridans
• Patient receiving therapeutic dexamethasone or • Note: Discontinue vancomycin after 72 h if
prednisone none of the above
• Infant ALL, ALL (Induction, Delayed Intensification), AML
• HSCT patient < 100 days from transplant —Consider stress-dose steroids
• If patient receiving systemic steroids ≥ 7 days
• If presentation within 4 weeks of ALL induction
Fig. 1.1 Emergency room algorithm for fever and neutropenia in pediatric oncology patients
a
see text for full detail as other treatment algorithms are equally justifiable
T&S type and screen, CBC complete blood count, PCR polymerase chain reaction, HSCT hematopoietic stem cell
transplant, ANC absolute neutrophil count, ALL acute lymphoblastic leukemia, AML acute myelogenous leukemia,
MRSA methicillin resistant S. aureus
1 Febrile Neutropenia 17
Admission
On-going reassessment
No Identified Yes
Pathogen‡
‡
Consult infectious disease and avoid monotherapy
• Consider infectious disease consult for the following:
• Consider potential antimicrobial modification: • Endovascular focus (persistent positive blood culture)
-- Add vancomycin if receiving monotherapy • Highly-resistant organism: ESBL-producing organism
-- Change to meropenem + amikacin and/or • MRSA: vancomycin or linezolid + aminoglycoside
fluoroquinolone • SPACEY (Serratia, Pseudomonas, Acinetobacter,
• Consider antifungal coverage if fevers persistent Citrobacter, Enterobacter, Yersinia): β-lactamase (+)
9
for ≥4 days and ANC < 0.5 x 10 /L • Enterococcus: ampicillin or vancomycin + aminoglycoside
• Consider checking relevant antibiotic drug • Fungus (particularly CNS)
levels if pathogen isolated • Streptococcus viridans: vancomycin + empiric antibiotics
• Listeria or Group B Streptococcus: ampicillin +
aminoglycoside
†Discharge Criteria • Clinical deterioration: shock
• Afebrile for 24 hours
• Negative blood culture for 48 hours
• No signs of localized or documented infection
• Performance status back to baseline
9
• ANC > 0.2 x 10 /L and rising steadily
• 24 hour caregiver whom:
-- is able to take patient’s temperature
-- lives within 1 hour of accessible medical care
-- has phone acess
-- has transportation at any time
Fig. 1.2 Inpatient algorithm for fever and neutropenia in pediatric oncology patients
a
see text for full detail as other treatment algorithms are equally justifiable
CVAD central venous access device, ANC absolute neutrophil count, MRSA methicillin resistant S. aureus
18 B.E. Gonzalez et al.
Persistent fever ≥4 days †Risk factors for invasive fungal infection (IFI):
Patient is considered High Risk if any of the following:
• Signs/symptoms of sepsis with neutropenic fever
9
• Prolonged fever and ANC <0.1 x 10 /L
• Mucositis
No Yes • Steroid or high-dose cytarabine therapy
ANC < 0.5 x 109/L • ALL (Induction, DI), AML, severe aplastic anemia
• Allogeneic HSCT patient < 100 days from transplant
• Prolonged use of total parenteral nutrition/lipids
• Prolonged use of broad-spectrum antibiotics
• Consult infectious disease • Previous IFI history
• Assess risk† • Active GVHD/prolonged immunosuppressive therapy
--Start antifungal therapy if IFI risk factors Consider Diagnostic
• Consider diagnostic work-up#: Workup# and
--CT sinus and chest Antifungal Therapy‡
--CT abdomen/pelvis (if focal exam)
--Ophthalmology exam
--Urine fungal screen
--Serum β-glucan & galactomannan
--Echocardiogram Discontinue fluconazole prophylaxis
--Biopsy notable lesions, if possible
--BAL galactomannan
Yes Identified No
Pathogen
‡ ‡Empiric
Pre-emptive and/or targeted antifungal therapy: antifungal therapy:
• Consult infectious disease • If positive galactomannan and/or high suspicion for
• Consider voriconazole levels if Aspergillus spp. Aspergillus spp., start voriconazole
• Consider combination antifungal therapy • Consider infectious disease consult
• Consider surgery and removal of foreign bodies • Note: ambisome empiric dosing versus treatment dosing
• Consider cytokine therapy therapy (G/GM-CSF) • Note: drug interactions with CSA, FK506
• Consider granulocyte infusions
• Note: drug interactions with CSA, FK506
Fig. 1.3 Antifungal algorithm for fever and neutropenia in pediatric oncology patients
a
see text for full detail as other treatment algorithms are equally justifiable
ANC absolute neutrophil count, ALL acute lymphoblastic leukemia, DI delayed intensification, AML acute myeloge-
nous leukemia, HSCT hematopoieic stem cell transplant, GVHD graft-versus-host disease, CT computed tomography,
BAL bronchoalveolar lavage, CSA cyclosporine, FK506 tacrolimus, bid twice daily
1 Febrile Neutropenia 19
Dommett R, Geary J, Freeman S et al (2009) Successful Gaur AH, Flynn PM, Heine DJ (2005) Diagnosis of
introduction and audit of a step-down oral antibiotic catheter-related bloodstream infections among pediat-
strategy for low risk paediatric febrile neutropaenia in ric oncology patients lacking a peripheral culture,
a UK, multicentre, shared care setting. Eur J Cancer using differential time to detection. Pediatr Infect Dis
45:2843–2849 J 24:445–449
Duncan C, Chisholm JC, Freeman S et al (2007) A pro- Gibson F, Chisholm J, Blandford E et al (2013) Developing
spective study of admissions for febrile neutropenia in a national ‘low-risk’ febrile neutropenia framework
secondary paediatric units in South East England. for use in children and young people’s cancer care.
Pediatr Blood Cancer 49:678–681 Support Care Cancer 21:1241–1251
Efrati O, Gonik U, Bielorai B et al (2007) Fiberoptic bron- Ginocchio F, Verrina E, Furfaro E et al (2012) Case report
choscopy and bronchoalveolar lavage for the evalua- of the reliability 1,3-beta-D-glucan monitoring during
tion of pulmonary disease in children with primary treatment of peritoneal candidiasis in a child receiving
immunodeficiency and cancer. Pediatr Blood Cancer continuous peritoneal dialysis. Clin Vaccine Immunol
48:324–329 19:626–627
El-Mahallawy HA, El-Wakil M, Moneer MM et al (2011) Glotzbecker B, Duncan C, Alyea E 3rd et al (2012)
Antibiotic resistance is associated with longer bactere- Important drug interactions in hematopoietic stem cell
mic episodes and worse outcome in febrile neutrope- transplantation: what every physician should know.
nic children with cancer. Pediatr Blood Cancer Biol Blood Marrow Transplant 18:989–1006
57:283–288 Goldberg E, Gafter-Gvili A, Robenshtok E et al (2008)
Everett ED, Pearson S, Rogers W (1979) Rhizopus surgi- Empirical antifungal therapy for patients with neutro-
cal wound infection with elasticized adhesive tape penia and persistent fever: systematic review and
dressings. Arch Surg 114:738–739 meta-analysis. Eur J Cancer 44:2192–2203
Feusner J, Cohen R, O’Leary M et al (1988) Use of rou- Gonzalez BE, Faverio LA, Marty FM et al (2011) Elevated
tine chest radiography in the evaluation of fever in serum beta-D-glucan levels in immunocompromised
neutropenic pediatric oncology patients. J Clin Oncol children with clinical suspicion for Pneumocystis jirove-
6:1699–1702 cii pneumonia. Clin Vaccine Immunol 18:1202–1203
Fisher BT, Zaoutis TE, Leckerman KH et al (2010) Risk Gøtzsche PC, Johansen HK (2002) Routine versus selec-
factors for renal failure in pediatric patients with acute tive antifungal administration for control of fungal
myeloid leukemia: a retrospective cohort study. infections in patients with cancer. Cochrane Database
Pediatr Blood Cancer 55:655–661 Syst Rev (2):CD000026
Fisher BT, Zaoutis TE, Park JR et al (2012) Galactomannan Greenberg D, Moser A, Yagupsky P et al (2005) Micro-
antigen testing for diagnosis of invasive Aspergillosis biological spectrum and susceptibility patterns of patho-
in pediatric hematology patients. J Pediatr Infect Dis gens causing bacteraemia in paediatric febrile neutropenic
1:116–124 oncology patients: comparison between two consecutive
Flynn PM (2009) Diagnosis and management of central time periods with use of different antibiotic treatment
venous catheter-related bloodstream infections in protocols. Int J Antimicrob Agents 25:469–473
pediatric patients. Pediatr Infect Dis J 28:1016–1017 Groll AH, Kurz M, Schneider W et al (1999) Five-year-
Fortun J, Grill F, Martin-Davila P et al (2006) Treatment survey of invasive aspergillosis in a paediatric cancer
of long-term intravascular catheter-related bacterae- centre. Epidemiology, management and long-term sur-
mia with antibiotic-lock therapy. J Antimicrob vival. Mycoses 42:431–442
Chemother 58:816–821 Groll AH, Castagnola E, Cesaro S et al (2014) Fourth
Freifeld AG, Bow EJ, Sepkowitz KA et al (2011) Clinical European Conference on Infections in Leukaemia
practice guideline for the use of antimicrobial agents (ECIL-4): guidelines for diagnosis, prevention, and
in neutropenic patients with cancer: 2010 update by treatment of invasive fungal diseases in paediatric
the Infectious Diseases Society of America. Clin patients with cancer or allogeneic haemopoietic stem-
Infect Dis 52:e56–e93 cell transplantation. Lancet Oncol 15:e327–e340
Furno P, Bucaneve G, Del Favero A (2002) Monotherapy Guy SD, Tramontana AR, Worth LJ et al (2012) Use of
or aminoglycoside-containing combinations for empir- FDG PET/CT for investigation of febrile neutropenia:
ical antibiotic treatment of febrile neutropenic patients: evaluation in high-risk cancer patients. Eur J Nucl
a meta-analysis. Lancet Infect Dis 2:231–242 Med Mol Imaging 39:1348–1355
Gassas A, Grant R, Richardson S et al (2004) Predictors Guyatt G, Gutterman D, Baumann MH et al (2006)
of viridans streptococcal shock syndrome in bactere- Grading strength of recommendations and quality of
mic children with cancer and stem-cell transplant evidence in clinical guidelines: report from an
recipients. J Clin Oncol 22:1222–1227 American College of Chest Physicians task force.
Gaur AH, Flynn PM, Giannini MA et al (2003) Difference Chest 129:174–181
in time to detection: a simple method to differentiate Hann I, Viscoli C, Paesmans M et al (1997) A comparison of
catheter-related from non-catheter-related blood- outcome from febrile neutropenic episodes in children
stream infection in immunocompromised pediatric compared with adults: results from four EORTC studies.
patients. Clin Infect Dis 37:469–475 International Antimicrobial Therapy Cooperative Group
1 Febrile Neutropenia 21
(IATCG) of the European Organization for Research and patients with invasive aspergillosis in the United
Treatment of Cancer (EORTC). Br J Haematol 99: States. Mycoses 54:e301–e312
580–588 Klaassen RJ, Goodman TR, Pham B et al (2000) “Low-risk”
Haroon A, Zumla A, Bomanji J (2012) Role of fluorine 18 prediction rule for pediatric oncology patients presenting
fluorodeoxyglucose positron emission tomography- with fever and neutropenia. J Clin Oncol 18:1012–1019
computed tomography in focal and generalized Klaassen IL, de Haas V, van Wijk JA et al (2011) Pyuria is
infectious and inflammatory disorders. Clin Infect Dis absent during urinary tract infections in neutropenic
54:1333–1341 patients. Pediatr Blood Cancer 56:868–870
Härtel C, Deuster M, Lehrnbecher T et al (2007) Current Klastersky J, Paesmans M, Rubenstein EB et al (2000)
approaches for risk stratification of infectious compli- The Multinational Association for Supportive Care in
cations in pediatric oncology. Pediatr Blood Cancer Cancer risk index: a multinational scoring system for
49:767–773 identifying low-risk febrile neutropenic cancer
Hennequin C, Ranaivoarimalala C, Chouaki T et al patients. J Clin Oncol 18:3038–3051
(2002) Comparison of aerobic standard medium with Klont RR, Mennink-Kersten MA, Verweij PE (2004) Utility
specific fungal medium for detecting fusarium spp in of Aspergillus antigen detection in specimens other than
blood cultures. Eur J Clin Microbiol Infect Dis 21: serum specimens. Clin Infect Dis 39:1467–1474
748–750 Koo S, Bryar JM, Page JH et al (2009) Diagnostic perfor-
Heussel CP (2011) Importance of pulmonary imaging mance of the (1 >3)-beta-D-glucan assay for invasive
diagnostics in the management of febrile neutropenic fungal disease. Clin Infect Dis 49:1650–1659
patients. Mycoses 54(Suppl 1):17–26 Kosmin AR, Fekete T (2008) Use of fungal blood cultures
Ho DY, Lin M, Schaenman J et al (2011) Yield of diag- in an academic medical center. J Clin Microbiol
nostic procedures for invasive fungal infections in 46:3800–3801
neutropenic febrile patients with chest computed Kourkoumpetis TK, Fuchs BB, Coleman JJ et al (2012)
tomography abnormalities. Mycoses 54:59–70 Polymerase chain reaction-based assays for the diag-
Hodgson-Viden H, Grundy PE, Robinson JL (2005) Early nosis of invasive fungal infections. Clin Infect Dis
discontinuation of intravenous antimicrobial therapy 54:1322–1331
in pediatric oncology patients with febrile neutrope- Lahoti A, Kantarjian H, Salahudeen AK et al (2010)
nia. BMC Pediatr 5:10 Predictors and outcome of acute kidney injury in
Jaijakul S, Vazquez JA, Swanson RN et al (2012) (1,3)-beta- patients with acute myelogenous leukemia or high-risk
D-Glucan as a prognostic marker of treatment response myelodysplastic syndrome. Cancer 116:4063–4068
in invasive candidiasis. Clin Infect Dis 55:521–526 Lalayanni C, Baliakas P, Xochelli A et al (2012) Outbreak
Jain P, Sandur S, Meli Y et al (2004) Role of flexible bron- of cutaneous zygomycosis associated with the use of
choscopy in immunocompromised patients with lung adhesive tape in haematology patients. J Hosp Infect
infiltrates. Chest 125:712–722 81:213–215
Jiancheng W, Minjun H, Yi-jun A et al (2009) Screening Lee DH, Vielemeyer O (2011) Analysis of overall level of
Pneumocystis carinii pneumonia in non-HIV-infected evidence behind Infectious Diseases Society of America
immunocompromised patients using polymerase practice guidelines. Arch Intern Med 171:18–22
chain reaction. Diagn Microbiol Infect Dis 64: Lehrnbecher T, Foster C, Vazquez N et al (1997) Therapy-
396–401 induced alterations in host defense in children receiv-
Johansen HK, Gøtzsche PC (2000) Amphotericin B lipid ing therapy for cancer. J Pediatr Hematol Oncol
soluble formulations versus amphotericin B in cancer 19:399–417
patients with neutropenia. Cochrane Database Syst Lehrnbecher T, Venzon D, de Haas M et al (1999)
Rev (3):CD000969 Assessment of measuring circulating levels of inter-
Jørgensen KJ, Gøtzsche PC, Johansen HK (2006) leukin-6, interleukin-8, C-reactive protein, soluble Fcγ
Voriconazole versus amphotericin B in cancer patients receptor type III, and mannose-binding protein in
with neutropenia. Cochrane Database Syst Rev febrile children with cancer and neutropenia. Clin
(1):CD004704 Infect Dis 29:414–419
Kalil AC (2011) Is cefepime safe for clinical use? A Lehrnbecher T, Stanescu A, Kuhl J (2002) Short courses
Bayesian viewpoint. J Antimicrob Chemother 66: of intravenous empirical antibiotic treatment in
1207–1209 selected febrile neutropenic children with cancer.
Karageorgopoulos DE, Vouloumanou EK, Ntziora F et al Infection 30:17–21
(2011) Beta-D-glucan assay for the diagnosis of inva- Lehrnbecher T, Phillips R, Alexander S et al (2012)
sive fungal infections: a meta-analysis. Clin Infect Dis Guideline for the management of fever and neutrope-
52:750–770 nia in children with cancer and/or undergoing hemato-
Kim PW, Wu YT, Cooper C et al (2010) Meta-analysis of poietic stem-cell transplantation. J Clin Oncol 30:
a possible signal of increased mortality associated 4427–4438
with cefepime use. Clin Infect Dis 51:381–389 Levine SJ, Kennedy D, Shelhamer JH et al (1992)
Kim A, Nicolau DP, Kuti JL (2011) Hospital costs and Diagnosis of Pneumocystis carinii pneumonia by mul-
outcomes among intravenous antifungal therapies for tiple lobe, site-directed bronchoalveolar lavage with
22 B.E. Gonzalez et al.
Paul M, Borok S, Fraser A et al (2005) Additional anti- Roberts SD, Wells GM, Gandhi NM et al (2012) Diagnostic
Gram-positive antibiotic treatment for febrile neutro- value of routine chest radiography in febrile, neutrope-
penic cancer patients. Cochrane Database Syst Rev nic children for early detection of pneumonia and
(3):CD003914 mould infections. Support Care Cancer 20:2589–2594
Paul M, Yahav D, Bivas A et al (2010) Anti-pseudomonal Rodriguez L, Ethier MC, Phillips B et al (2012) Utility of
beta-lactams for the initial, empirical, treatment of peripheral blood cultures in patients with cancer and
febrile neutropenia: comparison of beta-lactams. suspected blood stream infections: a systematic
Cochrane Database Syst Rev (11):CD005197 review. Support Care Cancer 20:3261–3267
Paul M, Dickstein Y, Schlesinger A et al (2013) Beta- Rolston KV (2005) Challenges in the treatment of infec-
lactam versus beta-lactam-aminoglycoside combina- tions caused by gram-positive and gram-negative bac-
tion therapy in cancer patients with neutropenia. teria in patients with cancer and neutropenia. Clin
Cochrane Database Syst Rev (6):CD003038 Infect Dis 40:S246–S252
Perfect JR, Dismukes WE, Dromer F et al (2010) Clinical Rosen GP, Nielsen K, Glenn S et al (2005) Invasive fungal
practice guidelines for the management of cryptococ- infections in pediatric oncology patients: 11-year
cal disease: 2010 Update by the Infectious Diseases experience at a single institution. J Pediatr Hematol
Society of America. Clin Infect Dis 50:291–322 Oncol 27:135–140
Petrilli AS, Carlesse FA, Pereira CA (2007) Oral gati- Rosenblum J, Lin J, Kim M et al (2013) Repeating blood
floxacin in the outpatient treatment of children with cultures in neutropenic children with persistent fevers
cancer fever and neutropenia. Pediatr Blood Cancer when the initial blood culture is negative. Pediatr
49:682–686 Blood Cancer 60:923–927
Pfeiffer CD, Fine JP, Safdar N (2006) Diagnosis of inva- Rybak MJ, Lomaestro BM, Rotschafer JC et al (2009)
sive aspergillosis using a galactomannan assay: a Vancomycin therapeutic guidelines: a summary of
meta-analysis. Clin Infect Dis 42:1417–1427 consensus recommendations from the Infectious
Phillips B, Wade R, Stewart LA et al (2010) Systematic Diseases Society of America, the American Society of
review and meta-analysis of the discriminatory perfor- Health-System Pharmacists, and the Society of
mance of risk prediction rules in febrile neutropaenic Infectious Diseases Pharmacists. Clin Infect Dis
episodes in children and young people. Eur J Cancer 49:325–327
46:2950–2964 Sahani DV, Kalva SP (2004) Imaging the liver. Oncologist
Phillips RS, Wade R, Lehrnbecher T et al (2012) 9:385–397
Systematic review and meta-analysis of the value of Sandoval C, Sinaki B, Weiss R et al (2012) Urinary tract
initial biomarkers in predicting adverse outcome in infections in pediatric oncology patients with fever
febrile neutropenic episodes in children and young and neutropenia. Pediatr Hematol Oncol 29:68–72
people with cancer. BMC Med 10:6 Santolaya ME, Cofre J, Beresi V (1994) C-reactive protein: a
Pizzo PA, Robichaud KJ, Gill FA et al (1982) Empiric valuable aid for the management of febrile children with
antibiotic and antifungal therapy for cancer patients cancer and neutropenia. Clin Infect Dis 18:589–595
with prolonged fever and granulocytopenia. Am J Med Santolaya ME, Villarroel M, Avendaño LF (1997)
72:101–111 Discontinuation of antimicrobial therapy for febrile,
Pizzo PA, Hathorn JW, Hiemenz J et al (1986) A random- neutropenic children with cancer: a prospective study.
ized trial comparing ceftazidime alone with combina- Clin Infect Dis 25:92–97
tion antibiotic therapy in cancer patients with fever Santolaya ME, Alvarez AM, Avilés CL et al (2002)
and neutropenia. N Engl J Med 315:552–558 Prospective evaluation of a model of prediction of inva-
Powers JH (2012) Editorial commentary: asking the right sive bacterial infection risk among children with cancer,
questions: morbidity, mortality, and measuring what’s fever, and neutropenia. Clin Infect Dis 35:678–683
important in unbiased evaluations of antimicrobials. Santolaya ME, Farfan MJ, De La Maza V et al (2011)
Clin Infect Dis 54:1710–1713 Diagnosis of bacteremia in febrile neutropenic epi-
Prasad P, Sun J, Danner RL et al (2012) Excess deaths sodes in children with cancer: microbiologic and
associated with tigecycline after approval based on molecular approach. Pediatr Infect Dis J
noninferiority trials. Clin Infect Dis 54:1699–1709 30:957–961
Raad I, Hanna HA, Alakech B et al (2004) Differential time to Scheinemann K, Ethier MC, Dupuis LL et al (2010)
positivity: a useful method for diagnosing catheter-related Utility of peripheral blood cultures in bacteremic pedi-
bloodstream infections. Ann Intern Med 140:18–25 atric cancer patients with a central line. Support Care
Raad I, Kassar R, Ghannam D et al (2009) Management Cancer 18:913–919
of the catheter in documented catheter-related Sekine L, Humbwavali J, Wolff FH et al (2010) Caspofungin
coagulase-negative staphylococcal bacteremia: versus liposomal amphotericin B: are they really com-
remove or retain? Clin Infect Dis 49:1187–1194 parable? Pediatr Infect Dis J 29:985–986
Rackoff WR, Gonin R, Robinson C et al (1996) Predicting Semeraro M, Thomée C, Rolland E et al (2010) A predic-
the risk of bacteremia in children with fever and neu- tor of unfavourable outcome in neutropenic paediatric
tropenia. J Clin Oncol 14:919–924 patients presenting with fever of unknown origin.
Reich HL, Williams Fadeyi D et al (2004) Nonpseudomonal Pediatr Blood Cancer 54:284–290
ecthyma gangrenosum. J Am Acad Dermatol Shenep JL, Flynn PM, Baker DK et al (2001) Oral cefix-
50:S114–S117 ime is similar to continued intravenous antibiotics in
24 B.E. Gonzalez et al.
the empirical treatment of febrile neutropenic children Theuretzbacher U (2012) Pharmacokinetic and pharma-
with cancer. Clin Infect Dis 32:36–43 codynamic issues for antimicrobial therapy in patients
Simon A, Fleischhack G, Hasan C et al (2000) Surveillance with cancer. Clin Infect Dis 54:1785–1792
for nosocomial and central line related infections Thomas KE, Owens CM, Veys PA et al (2003) The radio-
among pediatric hematology-oncology patients. Infect logical spectrum of invasive aspergillosis in children:
Control Hosp Epidemiol 21:592–596 a 10-year review. Pediatr Radiol 33:453–460
Smith PB, Benjamin DK Jr, Alexander BD et al (2007) Uhlenbrock S, Zimmermann M, Fegeler W et al (2001)
Quantification of 1,3-beta-D-glucan levels in children: Liposomal amphotericin B for prophylaxis of invasive
preliminary data for diagnostic use of the beta-glucan fungal infections in high-risk paediatric patients with
assay in a pediatric setting. Clin Vaccine Immunol chemotherapy-related neutropenia: interim analysis of
14:924–925 a prospective study. Mycoses 44:455–463
Son YM, Na SY, Lee HY et al (2009) Ecthyma gan- Uys A, Rapoport BL, Anderson R (2004) Febrile neutro-
grenosum: a rare cutaneous manifestation caused by penia: a prospective study to validate the Multinational
Stenotrophomonas maltophilia in a leukemic patient. Association of Supportive Care of Cancer (MASCC)
Ann Dermatol 21:389–392 risk-index score. Support Care Cancer 12:555–560
Spellberg B, Ibrahim A, Roilides E et al (2012) Uys A, Rapoport BL, Fickl H et al (2007) Prediction of out-
Combination therapy for mucormycosis: why, what, come in cancer patients with febrile neutropenia: com-
and how? Clin Infect Dis 54:S73–S78 parison of the Multinational Association of Supportive
Stabell N, Nordal E, Stensvold E et al (2008) Febrile neu- Care in Cancer risk-index score with procalcitonin,
tropenia in children with cancer: a retrospective C-reactive protein, serum amyloid A, and interleukins-1β,
Norwegian multicentre study of clinical and microbio- -6, -8 and -10. Eur J Cancer Care 16:475–483
logical outcome. Scand J Infect Dis 40:301–307 Vazquez JA (2008) Clinical practice: combination
Steinbach WJ (2011) Rational approach to pediatric anti- antifungal therapy for mold infections: much ado
fungal therapy. Adv Exp Med Biol 697:231–242 about nothing? Clin Infect Dis 46:1889–1901
Steinbach WJ, Addison RM, McLaughlin L et al (2007) Vidal L, Ben dor I, Paul M et al (2013) Oral versus
Prospective Aspergillus galactomannan antigen test- intravenous antibiotic treatment for febrile neutrope-
ing in pediatric hematopoietic stem cell transplant nia in cancer patients. Cochrane Database Syst Rev
recipients. Pediatr Infect Dis J 26:558–564 (10):CD003992
Sulahian A, Boutboul F, Ribaud P et al (2001) Value of Wacker P, Halperin DS, Wyss M et al (1997) Early
antigen detection using an enzyme immunoassay in hospital discharge of children with fever and neutro-
the diagnosis and prediction of invasive aspergillosis penia: a prospective study. J Pediatr Hematol Oncol
in two adult and pediatric hematology units during a 19:208–211
4-year prospective study. Cancer 91:311–318 Walsh TJ, Pappas P, Winston DJ et al (2002) Voriconazole
Sung L, Dupuis LL, Bliss B et al (2003) Randomized con- compared with liposomal amphotericin B for empiri-
trolled trial of once- versus thrice-daily tobramycin in cal antifungal therapy in patients with neutropenia and
febrile neutropenic children undergoing stem cell persistent fever. N Engl J Med 346:225–234
transplantation. J Natl Cancer Inst 95:1869–1877 Walsh TJ, Anaissie EJ, Denning DW et al (2008)
Sung L, Feldman BM, Schwamborn G et al (2004) Inpatient Treatment of aspergillosis: clinical practice guidelines
versus outpatient management of low-risk pediatric of the Infectious Diseases Society of America. Clin
febrile neutropenia: measuring parents’ and healthcare Infect Dis 46:327–360
professionals’ preferences. J Clin Oncol 22:3922–3929 Watt K, Benjamin DK Jr, Cohen-Wolkowiez M (2011)
Sung L, Phillips R, Lehrnbecher T (2011) Time for paedi- Pharmacokinetics of antifungal agents in children.
atric febrile neutropenia guidelines – children are not Early Hum Dev 87:S61–S65
little adults. Eur J Cancer 47:811–813 Wicki S, Keisker A, Aebi C et al (2008) Risk prediction of
Sung L, Manji A, Beyene J et al (2012) Fluoroquinolones fever in neutropenia in children with cancer: a step
in children With fever and neutropenia: a systematic towards individually tailored supportive therapy?
review of prospective trials. Pediatr Infect Dis Pediatr Blood Cancer 51:778–783
J 31:431–435 Wingard JR, Hiemenz JW, Jantz MA (2012) How I
te Poele EM, Tissing WJ, Kamps WA et al (2009) Risk assess- manage pulmonary nodular lesions and nodular
ment in fever and neutropenia in children with cancer: infiltrates in patients with hematologic malignancies
what did we learn? Crit Rev Oncol Hematol 72:45–55 or undergoing hematopoietic cell transplantation.
Teuffel O, Amir E, Alibhai SM et al (2011a) Cost- Blood 120:1791–1800
effectiveness of outpatient management for febrile Xu B, Shi P, Wu H et al (2010) Utility of FDG PET/CT in
neutropenia in children with cancer. Pediatrics guiding antifungal therapy in acute leukemia patients
127:e279–e286 with chronic disseminated candidiasis. Clin Nucl Med
Teuffel O, Ethier MC, Alibhai SM et al (2011b) Outpatient 35:567–570
management of cancer patients with febrile neutrope- Yahav D, Paul M, Fraser A et al (2007) Efficacy and
nia: a systematic review and meta-analysis. Ann Oncol safety of cefepime: a systematic review and meta-
22:2358–2365 analysis. Lancet Infect Dis 7:338–348
1 Febrile Neutropenia 25