REVIEW

CURRENT
OPINION Treatment of fever in neutropenia in pediatric
oncology patients
Thomas Lehrnbecher

Purpose of review
Fever during neutropenia is a common occurrence in children with cancer. A number of studies have
recently been performed to refine algorithms regarding initiation, modification, and termination of
antimicrobial treatment and are the basis for international pediatric-specific guidelines for the treatment of
fever and neutropenia in children with cancer.
Recent findings
Although hospitalization and prompt initiation of intravenous broad-spectrum antibiotics remains the
mainstay in the treatment of febrile neutropenic children with cancer, recent research has addressed a
number of questions to optimize the management of these patients. Risk prediction rules have been
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evaluated to allow for individualized treatment intensity and to evaluate the safety of early discontinuation
of empirical antibiotic therapy. In addition, the use of preemptive antifungal therapy has been evaluated
to decrease the use of antifungal agents.
Summary
Based on the results of studies in children, pediatric-specific guidelines have been established and are
regularly updated.
Keywords
bacterial infection, child, empirical treatment, febrile neutropenia, fungal infection

INTRODUCTION specific bacterial, viral, and fungal infections, as well

as the care of a clinically unstable patient are beyond
In children treated for a hematological malignancy
the scope of this work.
or a solid tumor, fever during neutropenia is a
common complication and a leading cause of emer-
gency department presentation [1,2]. Once hospi- INITIAL PRESENTATION OF A FEBRILE
talization of all neutropenic children with fever and NEUTROPENIC CHILD
prompt initiation of intravenous broad-spectrum
In all children presenting with febrile neutropenia, a
antibiotics which cover Gram-positive and Gram-
full history has to be taken (e.g., underlying malig-
negative pathogens including Pseudomonas aerugi-
nancy, last chemotherapeutic treatment, current
nosa had become standard of care, infection-related
medication) and a thorough physical examination
mortality in this patient population dramatically
has to be performed (e.g., skin, lung, blood pressure)
decreased. Although this strategy still applies for
[5]. In addition, according to international pediat-
most febrile neutropenic pediatric patients, recent ric-specific guidelines, blood cultures from all
studies that have refined algorithms regarding initi-
lumens of a central venous catheter should be
ation, modification, and termination of antimicro-
bial treatment have become the basis of
Pediatric Hematology and Oncology, Hospital for Children and Adoles-
international guidelines for the management of
cents, Johann Wolfgang Goethe-University, Frankfurt, Germany
fever and neutropenia in children with cancer or
Correspondence to Thomas Lehrnbecher, MD, Pediatric Hematology
following hematopoietic stem-cell recipients [3]. and Oncology, Hospital for Children and Adolescents, Johann Wolfgang
These pediatric-specific guidelines have recently Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
&
been updated [4 ]. This review highlights new Tel: +49 69 6301 83481; fax: +49 69 6301 6700;
aspects and ongoing controversies in the manage- e-mail: Thomas.Lehrnbecher@kgu.de
ment of children with febrile neutropenia, whereas Curr Opin Pediatr 2019, 31:35–40
antimicrobial prophylactic strategies, treatment of DOI:10.1097/MOP.0000000000000708

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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Hematology and oncology
KEY POINTS
 Hospitalization and prompt initiation of intravenous
broad-spectrum antibiotics remains the standard of care
in febrile neutropenic children.
 Risk application rules may help identify subgroups of
febrile neutropenic children for whom empirical
antibacterial therapy can be terminated early, who can
be treated in an outpatient setting, or who can receive
oral antibiotics without increasing morbidity and
mortality.
 Risk stratification rules for febrile neutropenic pediatric
patients need to be improved for wider application.
 The first study on preemptive antifungal therapy
suggests decreased antifungal use does not result in
increased mortality.
 Antibacterial and antifungal prophylaxis will become a
major challenge in the future (e.g., which patient
population should receive antimicrobial prophylaxis
with which compound versus emerging resistance).
obtained (strong recommendation, low-quality evi-
dence), whereas the need of additional peripheral
blood cultures is a matter of ongoing controversy
&
[4 ]. Although additional blood cultures from a
peripheral vein increase the likelihood of detecting
a true bacteremia compared with blood cultures
from a central venous catheter alone by 12% [95%
&
confidence interval (CI) 8–17%] [4 ], the impact on
outcome is unknown. In addition, the potential
benefit of peripheral blood cultures has to be bal-
anced against the pain and discomfort for the
patient. According to the pediatric-specific guide-
lines, chest radiography should be restricted to
patients with respiratory signs and symptoms, as
the rate of pneumonia in an asymptomatic febrile
neutropenic child is less than 3%, and no significant
adverse consequences occurred in asymptomatic
children who did not have a chest radiograph [6].
RISK PREDICTION RULES
In contrast to adult patients, there is not an inter-
nationally validated and generally applicable risk
prediction model available in the pediatric setting;
most models have inadequate sensitivity or fail to
identify a clinically meaningful number of low-risk
&
patients [7,8,9 ]. In addition, both pediatric and
adult risk prediction rules perform poorly in adoles-
cents and young adults [10]. In fact, a recent survey
demonstrated major inaccuracies in the clinical use
of risk prediction in pediatric cancer patients [11].
Thus, future work must focus on the development
and implementation of risk prediction rules that are
36 www.co-pediatrics.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
easily applicable and that will allow individualized
management of febrile neutropenic children and
adolescents (e.g., intensive antimicrobial treatment
in high-risk patients, reduced intensity in low-risk
patients).
EMPIRICAL ANTIBIOTIC THERAPY IN
CHILDREN PRESENTING WITH FEBRILE
NEUTROPENIA
The rapid institution of broad-spectrum antibiotics
has become the gold standard in the treatment of
febrile neutropenic cancer patients and is recom-
&
mended for both children and adults [4 ,12]. How-
ever, there is an ongoing discussion regarding what
empirical antibiotic treatment is appropriate for an
individual child, when and how the initial empirical
antibiotic therapy should be modified, and when to
stop empirical antibiotic treatment.
PEDIATRIC HIGH-RISK PATIENTS
The updated pediatric-specific guidelines recom-
mend initiation of empirical antibiotic monother-
apy using an antipseudomonal ß-lactam, a fourth-
generation cephalosporin, or a carbapenem for pedi-
atric high-risk febrile neutropenia (strong recom-
&
mendation, high-quality evidence) [4 ]. The
addition of a second Gram-negative agent or a gly-
copeptide should be reserved for special circumstan-
ces such as for children in whom a resistant
infection is suspected, for centers with a high rate
of resistant pathogens, as well as for children who
are clinically unstable. In this regard, a recent sys-
tematic review of randomized trials that compared
monotherapy with aminoglycoside-containing
combination therapy for pediatric febrile neutrope-
nia failed to demonstrate significant differences
between monotherapy and combination therapy
in failure rates, infection-related mortality, or over-
all mortality [13]. It is important to note that the
choice of empirical antibiotics needs to be regularly
adapted to local epidemiology and microbial resis-
tance patterns. Antibacterial prophylaxis, in partic-
ular with fluoroquinolones, may increase the
emergence of resistance [14]. A recent report from
the European Society for Pediatric Infectious Dis-
eases describes a dramatic increase in antibiotic-
resistant Gram-negative blood-stream infections in
children with cancer [15], which may become a
major challenge in the treatment of children with
febrile neutropenia. It should be noted that there is
not a clearly delineated percentage of resistant
pathogens that should prompt a change in the local
antibiotic strategy for febrile neutropenic patients.
The pediatric-specific guidelines recommend
Volume 31  Number 1  February 2019
 Treatment of fever in neutropenia in pediatric oncology patients Lehrnbecher
stopping double coverage for Gram-negative infec-
tion or with an empirical glycopeptide at 72 h, if the
patients clinically respond to therapy and if there is
no specific microbiologic finding that mandates
continuation of combination therapy.
PEDIATRIC LOW-RISK PATIENTS
In children with low-risk febrile neutropenia, who
comprise a relatively small group of patients inde-
pendent of risk stratification strategy, current pediat-
ric-specific guidelines give a weak recommendation
with a moderate-quality evidence to consider
initial or step-down outpatient management or
&
oral antibiotic administration [4 ]. Importantly, pre-
conditions such as a suitable infrastructure of the
center to ensure careful monitoring and follow-up
need to be considered and the absence of adequate
infrastructure may limit the application of this
strategy.
STOPPING EMPIRICAL ANTIBIOTICS
Empirical antibiotics can be stopped in all patients
who are afebrile for at least 24 h, have evidence of
hematological recovery, and in whom no pathogen
was isolated at 48 h (strong recommendation, low-
&
quality evidence) [4 ]. In low-risk patients without
microbiological or clinical documented infection,
the guidelines recommend that cessation of antibi-
otic treatment at 72 h be considered in those who
have been afebrile for at least 24 h, irrespective of
marrow recovery (weak recommendation, moder-
ate-quality evidence).
An interesting randomized study recently eval-
uated the safety and efficacy of withholding pro-
longed antimicrobial treatment in febrile
neutropenic pediatric patients with a proven respi-
&&
ratory viral infection [16 ]. Patients were tested at
admission for bacterial and viral pathogens,
including a PCR-microarray for 17 respiratory
viruses. Children positive for a respiratory virus
but negative for a bacterial pathogen who were
afebrile and in stable clinical condition after 48 h
of antimicrobial therapy were randomized to either
continue or to stop antimicrobials. This approach
was found to be safe without any deaths or signifi-
cant differences regarding bacterial infections or
admission rates to the ICU. The median duration of
antimicrobial use was significantly reduced from
7 days (range, 7– 9 days) to 3 days (3– 4 days). This
strategy seems feasible in the daily clinical practice,
but the results need to be validated in larger pro-
spective studies before this strategy can be incor-
porated into the international pediatric-specific
guidelines.
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FEBRILE NEUTROPENIA NOT RESPONDING
TO BROAD-SPECTRUM ANTIBIOTICS
When febrile neutropenia does not respond to
broad-spectrum antibiotics at 96 h, current pediat-
ric-specific guidelines recommend initiation of
empirical antifungal therapy in high-risk patients
(strong recommendation with high-quality evi-
&
dence) [4 ,17]. Patients at high-risk for invasive
fungal disease (IFD) are those with acute myeloid
leukemia; high-risk acute lymphoblastic leukemia
receiving intensive chemotherapy, relapsed acute
leukemia, and those undergoing allogeneic hemato-
poietic stem cell transplantation (HSCT). Patients
with additional risk factors such as high-dose steroid
exposure or older age may also be at higher risk for
IFD, although a threshold for steroid exposure and
age has not been defined to date [18]. There are also
reports that the individual risk of IFD is influenced
by other factors such as genetic polymorphisms [19].
DIAGNOSTIC CONSIDERATIONS IN
PERSISTENTLY FEBRILE NEUTROPENIC
CHILDREN
The concept of empirical antifungal therapy is based
on the observation that early diagnosis of IFD and
the prompt initiation of antifungal therapy improve
outcome [20]. On the contrary, it is extremely diffi-
cult to diagnose IFD at an early time point, in
particular in the pediatric setting. Clinical signs
and symptoms of IFD are often nonspecific and
cannot be distinguished from other causes, such
as bacterial or viral infection or complications of
the underlying disease itself. In contrast to Candida,
the most frequent pathogen of invasive mold infec-
tion, Aspergillus, can rarely be recovered from the
blood [21]. Therefore, there has been much effort
invested in the development and evaluation of vari-
ous nonculture-based assays such as the detection of
galactomannan or ß-D-glucan (BDG). Although gal-
actomannan is relatively specific for invasive asper-
gillosis, BDG may detect a wider array of pathogenic
fungi, including Aspergillus spp., Candida spp., Fusar-
ium spp., Trichosporon, or Pneumocystis jirovecii. A
recent systematic review that included eight studies
scrutinized the available data of serum galacto-
mannan and BDG in children with cancer or under-
going HSCT as a diagnostic tool, in persistently
febrile neutropenic patients or in patients with pul-
monary signs and symptoms [22]. In this setting,
pooled specificity and sensitivity were 85% (95% CI,
51–97%) and 89% (95% CI, 79–95%), which was
comparable with adult data [23]. Positive predictive
values (PPVs) of galactomannan in the diagnostic
setting were rather low and ranged between 0 and
100%, whereas the negative predictive values (NPVs)
www.co-pediatrics.com 37
Hematology and oncology
were considerably higher, ranging from 70 to 100%.
Only limited data for BDG were available for children,
and for the three pediatric studies analyzed, wide
ranges were found for specificity (29–82%), sensitiv-
ity (50–83%), PPV (17–49%), and NPV (84–96%),
respectively [22]. Notably, antifungal prophylaxis
seems to significantly increase false-negativity of
the nonculture-based assays [24]. Imaging, in partic-
ular chest computed tomography (CT) scan, is
another important diagnostic tool in the early detec-
tion of IFD. However, the ‘halo sign’, the ‘air-crescent
sign’, or ‘cavitation’ which are considered typical
signs of pulmonary aspergillosis are infrequently seen
in pediatric patients [25]. A retrospective study in 139
children with invasive aspergillosis found the halo
sign in 6.4%, the air-crescent sign in 1.6%, and cavi-
tation in 14.4% of the patients [26]. In contrast,
nodules were detected in 21% of the children.
EMPIRICAL ANTIFUNGAL THERAPY
Due to the difficulties to early and reliably diagnose
or exclude IFD, empirical antifungal therapy became
the standard of care for pediatric patients with per-
sistent febrile neutropenia unresponsive to appropri-
ate empirical antibacterial therapy. Although this
concept results in patient overtreatment, a meta-
analysis in adults demonstrated that empirical anti-
fungal therapy significantly decreased IFDs as com-
pared with no treatment [27]. For children and
adolescents, caspofungin (50 mg/m2/day; day 1,
70 mg/m2; maximum 70 mg/day) and liposomal
amphotericin B (L-AmB, 1–3 mg/kg/day) are cur-
rently recommended for empirical antifungal ther-
apy, and both compounds are approved for this
&
indication for pediatric and adult patients [4 ,17].
The three studies in children on which the pediatric
recommendations are originally based demonstrated
that caspofungin was as effective as L-AmB, and that
L-AmB was less nephrotoxic than amphotericin B
deoxycholate [28–30]. The results of the pediatric
studies favorably compare with the much larger data-
sets in adults. In the absence of suspected or docu-
mented IFD, empirical antifungal therapy should be
continued until the resolution of neutropenia.
Although not investigated in prospective studies,
switching to a different class of mold-active antifun-
gal agents seems reasonable in patients already
receiving mold-active antifungal prophylaxis.
In contrast to children at high-risk for IFD, one
can consider withholding empirical antifungal ther-
apy in patients at low-risk for IFD, for example,
children with a solid tumor, brain tumor, or Hodg-
kin lymphoma. This recommendation, which was
based on a single pediatric study with a low number
of patients, has been added to the updated pediatric-
38 www.co-pediatrics.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
specific guidelines as a weak recommendation with
&
a low-quality evidence [4 ,31]. Importantly, as low
risk for IFD is not equal to no risk, empirical anti-
fungal therapy may be beneficial in selected low-risk
patients with additional risk factors.
PREEMPTIVE ANTIFUNGAL THERAPY
As the approach of empirical antifungal treatment is
associated with an overtreatment of a number of
patients leading to an increase in adverse events,
prolonged hospitalization, and higher cost, there
was much interest in the evaluation of preemptive
antifungal therapy [32]. In contrast to empirical
antifungal treatment, in which antifungal therapy
is given to all persistently febrile neutropenic
patients at high-risk for IFD, preemptive therapy
applies an additional complete screening program
that includes biomarkers and imaging. Using this
approach, only patients in whom these additional
diagnostics suggest IFD receive antifungal therapy.
The preemptive antifungal strategy decreases the
number of patients treated compared with the
empirical approach. However, as shown in a study
in adults, the preemptive treatment increases the
incidence of IFD, albeit without increasing mortality
while decreasing the overall costs of antifungal
drugs [33]. Results from a prospective randomized
study of empirical (n ¼ 73) versus preemptive anti-
fungal (n ¼ 76) treatment in persistently febrile neu-
tropenic children at high-risk for IFD, in whom
clinical, laboratory (including absolute neutrophil
and monocyte count, C-reactive protein), imaging
(including chest and sinus CT scan, abdominal
ultrasound), or microbiological (including blood
culture, galactomannan) criteria suggested IFD were
&&
published recently [34 ]. Children receiving anti-
fungal prophylaxis with voriconazole or posacona-
zole and children undergoing HSCT were excluded.
For both the empirical and preemptive arms, anti-
fungal agents included L-AmB, an echinocandin, or
voriconazole. The percentage of children with IFD as
well as IFD-related mortality was the same in both
settings (12 and 3%, respectively), but the median
duration of antifungal therapy was significantly
lower in the preemptive arm (6 days) as compared
with the empirical arm (11 days). The authors con-
cluded that in persistently febrile neutropenic chil-
dren, preemptive antifungal therapy is as effective as
empirical antifungal treatment, and significantly
reduces the use of antifungal drugs. However, this
approach should be validated, preferably in an inter-
national multicenter study, before the guidelines are
modified to recommend this strategy. Furthermore,
the value of preemptive antifungal therapy remains
unclear in children at high-risk for IFD who receive
Volume 31  Number 1  February 2019
 Treatment of fever in neutropenia in pediatric oncology patients Lehrnbecher
Table 1. Research gaps in the treatment of children with
febrile neutropenia
Research gaps
Development and evaluation of risk prediction rules for different
age groups
Identification of patient populations in which early cessation of
antibiotic therapy is safe
Development and evaluation of early markers of invasive fungal
infection
Comparison of empirical and preemptive antifungal therapy in a
multinational setting
antifungal prophylaxis, which is a common stan-
dard in many centers.
CONCLUSION
Although hospitalization and prompt initiation of
broad-spectrum antibiotics will remain the mainstay
in the treatment of most children and adolescents
presenting with febrile neutropenia, current and
ongoing research is addressing a number of questions
that will optimize the management of these patients
(Table 1). For example, risk prediction rules that are
being designed and evaluated, may allow a less inten-
sive management in low-risk patients. In addition,
studies to investigate the patient population(s) in
which it is safe to stop antibacterial treatment early
(e.g., prior to marrow recovery), or how to better
stratify patients who may benefit from antifungal
compounds, will hopefully lead to a decreased use
of antimicrobial agents without negatively impact-
ing patient outcome. At the same time, emerging
resistance, both for bacterial and fungal pathogens,
will remain a continuous challenge.
Acknowledgements
None.
Financial support and sponsorship
T.L. has received research grants from Gilead Sciences, is
a consultant to Astellas, Basilea, Gilead Sciences, and
Merck/MSD, and is on the speaker’s bureau of Astellas,
Gilead Sciences, Merck/MSD, and Pfizer.
Conflicts of interest
There are no conflicts of interest.
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Volume 31  Number 1  February 2019