Clinical Microbiology and Infection 23 (2017) 173e178

Contents lists available at ScienceDirect

Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Original article

Efficacy and safety of withholding antimicrobial treatment in children

with cancer, fever and neutropenia, with a demonstrated viral
respiratory infection: a randomized clinical trial
M.E. Santolaya 1, 7, A.M. Alvarez 3, 7, M. Acun~ a 4, 7, C.L. Avile
s 5, 7, C. Salgado 6, 7,
J. Tordecilla , M. Varas , M. Venegas , M. Villarroel , M. Zubieta 6, 7, A. Toso 1,
4, 7 3, 7 3 1, 7

n 1, V. de la Maza 1, A. Vergara 2, R. Valenzuela 1, J.P. Torres 1, *

A. Bataszew 1, M.J. Farfa
1)
Department of Paediatrics, Hospital Dr Luis Calvo Mackenna, Faculty of Medicine, Universidad de Chile, Santiago, Chile
2)
Centre for Molecular Studies, Hospital Dr Luis Calvo Mackenna, Faculty of Medicine, Universidad de Chile, Santiago, Chile
3)
Department of Paediatrics, Hospital San Juan de Dios, Faculty of Medicine, Universidad de Chile, Santiago, Chile
4)
Department of Paediatrics, Hospital Dr Roberto del Río, Faculty of Medicine, Universidad de Chile, Santiago, Chile
5)
Department of Paediatrics, Hospital San Borja Arriaran, Faculty of Medicine, Universidad de Chile, Santiago, Chile
6)
Department of Paediatrics, Hospital Dr Exequiel Gonza lez Cort
es, Santiago, Chile
7)
Committee of Infectious Diseases, National Child Programme of Antineoplastic Drugs Network, Santiago, Chile

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To determine efficacy and safety of withholding antimicrobials in children with cancer, fever
Received 17 August 2016 and neutropenia (FN) with a demonstrated respiratory viral infection.
Received in revised form Methods: Prospective, multicentre, randomized study in children presenting with FN at five hospitals in
3 November 2016
Santiago, Chile, evaluated at admission for diagnosis of bacterial and viral pathogens including PCR-
Accepted 4 November 2016
microarray for 17 respiratory viruses. Children positive for a respiratory virus, negative for a bacterial
Available online 14 November 2016
pathogen and with a favourable evolution after 48 h of antimicrobial therapy were randomized to either
Editor: L. Leibovici maintain or withhold antimicrobials. Primary endpoint was percentage of episodes with uneventful
resolution. Secondary endpoints were days of fever/hospitalization, bacterial infection, sepsis, admission
Keywords: to paediatric intensive care unit (PICU) and death.
Antimicrobials Results: A total of 319 of 951 children with FN episodes recruited between July 2012 and December 2015
Cancer had a respiratory virus as a unique identified microorganism, of which 176 were randomized, 92 to
Children maintain antimicrobials and 84 to withdraw. Median duration of antimicrobial use was 7 days (range 7
Febrile neutropenia
e9 days) versus 3 days (range 3e4 days), with similar frequency of uneventful resolution (89/92 (97%)
Respiratory viral infection
and 80/84 (95%), respectively, not significant; OR 1.48; 95% CI 0.32e6.83, p 0.61), and similar number of
days of fever (2 versus 1), days of hospitalization (6 versus 6) and bacterial infections throughout the
episode (2%e1%), with one case of sepsis requiring admission to PICU in the group that maintained
antimicrobials, without any deaths.
Conclusions: The reduction of antimicrobials in children with FN and respiratory viral infections, based
on clinical and microbiological/molecular diagnostic criteria, should favour the adoption of evidence-
based management strategies in this population. M.E. Santolaya, CMI 2017;23:173
© 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction (FN) [1e3]. Episodes of FN during chemotherapy are currently

managed within the hospital with broad-spectrum antimicrobial
Children with cancer are exposed to viral, bacterial and fungal therapy [4,5]. Until recently, the most common aetiological agents
infections, especially during the episodes of fever and neutropenia reported in FN episodes occurring in children with cancer have
been bacterial and fungal pathogens. Viral infections, particularly
* Corresponding author. J.P. Torres, Division of Paediatric Infectious Diseases, respiratory viruses, have been increasingly recognized as signifi-
Department of Paediatrics, Faculty of Medicine, University of Chile, Hospital Luis cant aetiological agents of FN in this population [6,7].
Calvo Mackenna, Antonio Varas 360, Providencia, Santiago, Chile.
E-mail address: jptorres@clc.cl (J.P. Torres).

http://dx.doi.org/10.1016/j.cmi.2016.11.001
1198-743X/© 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
174 M.E. Santolaya et al. / Clinical Microbiology and Infection 23 (2017) 173e178

Respiratory viral infections are a leading cause of morbidity and cancer [1]. Briefly, children were hospitalized and low-risk FN ep-
mortality in immunocompetent children [8,9]. In paediatric pa- isodes were treated with a third-generation cephalosporin (ceftri-
tients with cancer, respiratory viruses can be detected in up to 57% axone) whereas children at high risk were treated with an anti-
of episodes of FN [6,7,10e15]. In a previous study we determined pseudomonal third-generation cephalosporin (ceftazidim) plus
the frequency and clinical outcome of respiratory virus-positive FN amikacin with or without an anti-Gram-positive b-lactam or
episodes [6]. Respiratory viruses were the most common agents glycopeptide antimicrobial therapy.
detected and clinical outcomes of these episodes were significantly After 48 h of hospitalization (day 3) children with a nasopha-
better than episodes with single bacterial infections or vir- ryngeal sample positive for a respiratory virus, absence of any
alebacterial co-infections. Children with respiratory viral infections positive bacterial culture and with a favourable clinical evolution,
had fewer days of hospitalization, a lower probability of haemo- were subject to a 1:1 simple randomization by the study coordi-
dynamic instability and lower rates of admission to the paediatric nator (blinded) using statistical software (GRAPHPAD PRISM, version
intensive care unit (PICU) [6]. 6.01; GraphPad, San Diego, CA, USA) into two groups: maintenance
For children with FN most research efforts have focused on of antimicrobials until the end of the febrile episode, and the
management of bacterial and fungal infections, mainly in pro- intervention group in which antimicrobials were withdrawn. Ac-
posing models of risk prediction for invasive bacterial and fungal cording to ethical committee requirements, it was possible to
infections [16e23], improvements in the molecular diagnosis of randomize each child in only one episode of FN that met the study
infections [24,25] and selective antimicrobial management in criteria, for this reason, one randomized episode of FN was equiv-
children with high-risk and low-risk FN episodes [18,26]. In alent to one randomized patient.
contrast with the increase in studies of bacterial and fungal in- Both groups were monitored daily for clinical and laboratory
fections in this population, studies of viral infections are scarce evolution until fever resolution and ANC 500/mm3. Children with
and have been recognized as a research gap in the field [1]. A a bacterial pathogen or children in whom all studies gave negative
rational approach towards the management of a potential infec- results continued their antimicrobial management according to
tion in children with cancer and FN requires a comprehensive current standard of care. In the antimicrobial withdrawal group,
analysis of all microbiological agents involved. Implementation of criteria for re-instalment antimicrobial therapy were: resurgence
a systematic study and early detection of respiratory viral infec- of fever, clinical worsening or new clinical and/or laboratory find-
tion in children with cancer and FN might help to optimize their ings suggesting a bacterial infection. One blinded investigator
management by reducing hospitalization and antimicrobial use. evaluated all cases after discharge, deciding that outcome was
In this study we aim to determine the efficacy and safety of uneventful or not, without access to information about the specific
withholding antimicrobial treatment 48 h after admission in chil- intervention of each child (see Definitions). In children that
dren with cancer and FN, with a demonstrated respiratory viral continued with antimicrobial therapy, the standard duration of
infection and a favourable clinical course. therapy was 7 days. Antimicrobials were stopped at day 7 if chil-
dren had a favourable evolution, with at least a full day without
Patients and methods fever and two consecutives CRP values
40 mg/L. The ANC was not
a criterion for stopping antimicrobial therapy.
Population
Study endpoints
From July 2012 to December 2015, a prospective, randomized,
multicentre, government-sponsored study was conducted in five
The primary endpoint between the group that maintained an-
participating hospitals in Santiago, Chile, belonging to the National
timicrobials and the group with antimicrobial withholding was
Child Programme of Antineoplastic Drugs network. Children and
number (%) of episodes with uneventful resolution. The secondary
adolescents with cancer
18 years of age admitted with an episode
endpoints were (a) number of days of fever, (b) number of days of
of FN were enrolled after parental and child signed informed con-
hospitalization, (c) percentage of episodes that develop a demon-
sent and assent (if older than 8 years of age). Children with hae-
strated or probable invasive bacterial infection, (d) re-instalment of
matopoietic stem cell transplants were excluded. This study was
antimicrobial therapy, (e) sepsis during hospitalization, (f) admis-
approved by the ethics committee of each participating institution.
sion to the PICU, (g) death.
Overall study design
Laboratory evaluation
Children were evaluated at admission to characterize the febrile
episode, establish their risk for invasive bacterial infection and Laboratory tests. Haematological, biochemical and microbio-
perform a common protocol for diagnosis of bacterial and viral logical tests were performed at each hospital according to standard
pathogens. We recorded age, gender, type of cancer, type and date techniques.
of the last chemotherapy, use of granulocyte colony-stimulating Molecular detection for respiratory viruses. Detection was per-
factor, use of antimicrobial prophylaxis, use of central venous formed on nasopharyngeal samples collected from all children at
catheter, hours of fever before admission, axillary temperature, the time of admission (Copan™ flocked swabs, Brescia, Italy). The
blood pressure, heart rate, respiratory rate, signs and symptoms swab was inserted into a vial containing viral transport medium
indicative of an infectious focusdespecially respiratory signs/ (UTM-RT, Copan™), transported to the central laboratory and
symptoms, haematological status (absolute neutrophil count stored at e80 C until analysis in the next 24 h after admission. Total
(ANC), haemoglobin level, platelet count), biochemical tests, nucleic acid was extracted (easyMAG NucliSens; BioMe rieux,
quantitative C reactive protein (CRP), central and peripheral auto- Durham, NC, USA) and tested for 17 respiratory viruses (influenzas
mated blood cultures, other cultures if clinically indicated, and a A, B, C; parainfluenzas 1, 2, 3, 4a and 4b; respiratory syncytial virus
molecular-based evaluation for respiratory viruses. (RSV) A and B; rhinovirus; adenovirus; echovirus; human bocavi-
After initial evaluation, all children were treated following the rus; coronavirus; human metapneumoviruses A and B) by
Latin American Consensus for a Rational Approach of Children with multiplex-PCR low-density microarray, according to the manufac-
FN [27] and Guidelines for the management of FN in children with turer’s instructions (PneumoVir; Genomica, Madrid, Spain).
 M.E. Santolaya et al. / Clinical Microbiology and Infection 23 (2017) 173e178 175

Definitions. (a) neutropenia: ANC
500/mm3; (b) fever: single criteria and 5/170 (3%) had incomplete data. The 951 episodes
axillary temperature 38.5 C, or 38 C in two measurements enrolled were evaluated for bacterial and viral infections and all
separated by at least 1 h; (c) high-risk FN: an FN episode with one of received empiric antimicrobial therapy. In all, 319 (34%) had a
the following factors at the time of admission: (i) relapse of positive nasopharyngeal sample for respiratory viruses at admis-
leukaemia as cancer type, (ii) hypotension or (iii) quantitative CRP sion and were negative for a bacterial pathogen. Forty-eight hours
90 mg/L, or with the following two factors: (iv)
7 days between later, 176/319 (55%) of these episodes met all criteria for randomi-
the last chemotherapy and the beginning of the fever and (v) zation, of which 92/176 (52%) were randomized into a current
platelet count
50 000/mm3; (d) low-risk FN: an FN episode antimicrobial management and 84/176 (48%) into antimicrobial
without the above mentioned factors; (e) episodes with favourable withholding. At the time of randomization, median ANC was 132/
evolution after 48 h of antimicrobial therapy: good clinical condi- mm3 and 207/mm3 in the maintenance and withholding antimi-
tion (subjective evaluation of the clinical condition by the attending crobial groups, respectively (p 0.15), with 87% and 80% of children
physician), temperature
38 C, absence of an identifiable new having an ANC
500/mm3 in each group (p 0.3). From 143 episodes
clinical focus and CRP <90 mg/L; (f) uneventful resolution: positive for a respiratory virus and negative for a bacterial pathogen
favourable resolution of the FN episode according to the random- not randomized, 109 did not have a favourable evolution after 48 h
ized intervention, without changes in the therapy in the group that of antimicrobial therapy (104 maintain fever or CRP 90 mg/L, five
maintain antimicrobials and without re-instalment in the group had haemodynamic instability), 21 had new clinical foci and 13
with antimicrobial withholding; (g) demonstrated/probable inva- were not randomized by no adherence to the protocol (Fig. 1).
sive bacterial infection: bacteraemia or isolation of bacteria from a Table 1 describes the main characteristics of children with epi-
normally sterile site, or clinical signs suggestive of a localized sodes of FN and a positive respiratory viral infection randomized to
bacterial infection, with parenchymal involvement, with or without both groups. Age, gender, type of cancer and other characteristics
microbiological isolation; (h) sepsis: systemic inflammatory were similar between the two groups (p NS). Less than 10% of
response syndrome, accompanied by abnormal tissue perfusion, children in each group received prophylaxis other than
caused by a presumptive bacterial infection, with or without trimethoprim-sulfamethoxazole for Pneumocystis jirovecii. Eighty-
microbiological confirmation, (i) respiratory viral infection: detec- eight of 176 episodes (50%) had a high-risk FN. Of the 176 epi-
tion of at least one respiratory virus in nasopharyngeal sample by sodes randomized, 65/92 (71%) and 66/84 (78%), respectively, had
PCR; (j) upper/lower respiratory viral infection: infection of respi- clinical characteristics suggesting an upper/lower respiratory tract
ratory tract that clinically affects from the larynx toward proximal infection at the time of admission.
or beyond the larynx plus respiratory viral infection, respectively.
Outcome of children with FN episodes by study groups
Sample size and statistical analysis
Table 2 shows the outcome of 176 randomized children, ac-
Sample size. The primary endpoint for this non-inferiority cording to intervention. As expected, median durations of antimi-
study was number (%) of episodes with uneventful resolution. crobial therapy were significantly different in children that
Sample size was calculated based on the hypothesis that the fre- maintained (7 days, interquartile range (IQR) 7e9 days) compared
quency of occurrence of uneventful resolution was the same for with children in whom antimicrobials were withdrawn (3 days, IQR
both groups. Considering an unfavourable outcome of 10% as pre- 3e4 days), p <0.0001. Percentages of episodes of FN with un-
viously reported for this population, a maximum acceptable dif- eventful resolution were 89/92 (97%) and 80/84 (95%), respectively
ference of 10% between groups, a type I error of 0.05 and a potency (p NS), OR 1.48. (95% C.I. 0.32e6.83), p 0.61. Days of fever (2 and 1),
of 90%, we calculated that 134 episodes were required, 67 in the days of hospitalization (6 and 6) and development of a demon-
group that maintain antimicrobial therapy and 67 in the antimi- strated/probable invasive bacterial infection (2% and 1%) were
crobial withholding group. The overall capacity of enrolment in the similar among groups. No deaths occurred.
five study sites was estimated in 300 episodes per year (25/month). Three children had a demonstrated/probable bacterial infection,
Our enrolment was estimated for a total of 1000 FN episodes in the two had bacteraemia caused by extended spectrum b-lactamase-
study period. positive Klebsiella pneumoniae in the group maintaining antimi-
crobials and one case of a culture-negative sinusitis in the antimi-
Statistical analysis crobial withholding group. Re-instalment of antimicrobial therapy
was indicated in four children. All four had acute myeloid
Categorical variables were compared with chi-square test or leukaemia, were admitted with a high-risk FN and met study
Fisher exact test depending on the number of episodes per com- criteria for upper respiratory viral infection. In the four cases where
parison group. Continuous variables were compared between the antimicrobials were discontinued with children in good clinical
two groups according to their distribution(Student’s t or Man- conditions, temperature <38 C and CRP <90 mg/L, according to the
neWhitney U test).The risk for an uneventful resolution was eval- protocol; three of them presented with fever between days 5 and 7
uated between the exposed and unexposed groups calculating the after admission, without identifiable new foci or clinical deterio-
OR with the respective 95% CI. Statistical analyses were performed ration and with CRP <90 mg/L. The clinical course was favourable in
with the SIGMA STAT 3.0 Program and SYSTAT software, CA, USA. three of the children with fever declining after one day of new
antimicrobial therapy, in the absence of any bacterial pathogen
Results detection. The fourth child developed fever on day 5 and an in-
crease in CRP to 100 mg/L. Clinical and imaging findings suggested
Population characteristics sinusitis requiring a 14-day antimicrobial therapy. The child did not
develop sepsis and was not admitted to PICU. He was discharged
Between July 2012 and December 2015, a total of 1121 episodes with a diagnosis of probable invasive bacterial infection.
of FN were evaluated in the five hospitals participating in the study, One child from the group that maintained antimicrobials
of which 951 (85%) episodes were enrolled and 170 (15%) were developed sepsis and was admitted to the PICU. She was a 3-year-
excluded, because 97/170 (57%) children and their parent refused to old girl with a neuroblastoma, a high-risk FN and an upper respi-
participate, 68/170 (40%) episodes did not meet the inclusion ratory infection. On the day of randomization, she was afebrile and
176 M.E. Santolaya et al. / Clinical Microbiology and Infection 23 (2017) 173e178

Febrile Neutropenia
D Episodes
A (n=1121)
Y

Enrolled
Episodes
(n=951)

D
A No pathogen Respiratory Virus (+) Respiratory Virus (–) Respiratory Virus (+)
Y detected Bacteria (–) Bacteria (+) Bacteria (+)
(n=356) (n=319) (n=154) (n=122)
2

Randomized
D Episodes
A (n=176)
Y

3
Maintain Withhold
antimicrobial antimicrobial
therapy therapy
(n=92) (n=84)

Fig. 1. Episodes of fever and neutropenia evaluated, enrolled and randomized during study period.

CRP value was 14 mg/L. On day 6 she presented with fever and
haemodynamic instability. Blood cultures obtained at day 6 were
Table 1 positive for an extended spectrum b-lactamase-positive Klebsiella
Admission characteristics of 176 episodes of fever and neutropenia in children with a
pneumoniae, CRP value increased up to 250 mg/L and she was
demonstrated respiratory viral infection, according to intervention
admitted to PICU receiving antimicrobials based on the bacterial
Characteristics Type of intervention p isolation for a new period of 14 days, with good clinical outcome.
Maintain Antimicrobial No deaths occurred among the 176 randomized children during the
antimicrobial withholding study period.
n ¼ 92 n ¼ 84 We performed a separated analysis of the 176 episodes ran-
Age in years, median (IQR) 5 (3e9) 4 (3e8) 0.57
domized according to the risk status for invasive bacterial infection
Male gender, n (%) 40 (44) 46 (55) 0.13 determined at admission. For the 88 children with episodes of low-
Type of cancer, n (%) risk FN the median durations of antimicrobial therapy were 7 days
Leukaemia/Lymphoma 49 (53) 55 (66) 0.09 (IQR 7e9) and 3 days (IQR 3e3), p <0.001; with 98% and 100% of
Leukaemia relapse 7 (8) 4 (5) 0.43
episodes with uneventful resolution, without cases of antimicrobial
Solid tumours 36 (39) 25 (29) 0.19
High risk for invasive 43 (47) 45 (54) 0.36 re-instalment, development of sepsis and admission to PICU. In the
bacterial infection, n (%) 88 episodes of high-risk FN, the median durations of antimicrobial
Use of G-CSF, n (%) 27 (29) 26 (31) 0.81 therapy were 7 days (IQR 7e9) and 4 days (IQR 3e5), p <0.001, with
Use of CVC, n (%) 77 (84) 68 (81) 0.63 93% of episodes with uneventful resolution in both groups, with the
Hours of fever previous to 2 (1e4) 2 (1e3) 0.10
admission, median (IQR)
four cases of antimicrobial re-instalment and one case of sepsis and
Admission clinical diagnosis, n (% ) admission to PICU, all of them described previously.
Fever without focus 19 (20) 13 (16) 0.37
Upper respiratory infection 42 (46) 44 (52) 0.37
Respiratory viruses identified in each study group
Lower respiratory infection 23 (25) 22 (26) 0.85
Intestinal focus 6 (7) 5 (6) 0.87
Othersa 2 (2) 0 The main respiratory viruses identified in the 176 children
G-CSF: granulocyte-colony stimulating factor; CVC: central venous catheter; IQR:
randomized with episodes of FN are described in Table 3. Overall,
Interquartile range the most common respiratory virus was rhinovirus (41%) followed
a
Others: Skin/soft tissue infection by RSV, parainfluenza virus and influenza virus with no differences
 M.E. Santolaya et al. / Clinical Microbiology and Infection 23 (2017) 173e178 177

Table 2 We previously demonstrated that it was possible to apply se-

Outcome of 176 children with fever, neutropenia and a demonstrated respiratory lective management, proposing ambulatory therapy in children
viral infection, according to intervention
with low-risk FN, defined according to the following parameters:
Characteristics Type of intervention Total p type of cancer, haemodynamic stability, CRP values, platelet count
Maintain Antimicrobial and number of days since the last chemotherapy [26]. In this study,
antimicrobial withholding we advance a step further, including the possibility of stopping
n ¼ 92 n ¼ 84 antimicrobial therapy 48 h after admission in children with a
positive respiratory viral infection, a negative bacterial infection
Days of antimicrobial therapy, 7 (7e9) 3 (3e4) 6 (3e7) < 0.0001
median (IQR) and a favourable clinical course, including episodes with low and
Days of fever after admission, 2 (1e3) 1 (1e2) 1 (1e2) 0.44 high risk for invasive bacterial infection.
median (IQR) Knowledge on the epidemiology of respiratory viral infection in
Days of hospitalization, 6 (4e8) 6 (4e7) 6 (4e7) 0.65 immunocompromised children is scarce with few systematic
median (IQR)
Days of ANC <500/mm3, 5 (3e8) 4 (3e8) 5 (3e8) 0.23
studies aimed to determine their clinical impact [6]. RSV, influenza
median (IQR) virus, parainfluenza virus, adenovirus and picornaviruses have
Days of AMC <100/mm3, 3 (0e6) 2 (0e5) 3 (0e5) 0.46 been the most common aetiological agents detected in this popu-
median (IQR) lation [6,7,12]. The increasing detection of viruses highlights the
Resolving uneventfully, n (%) 89 (97) 80 (95) 169 (96) 0.61
relevance of optimizing viral diagnosis in children with FN [1].
Demonstrated/probable 2 (2) 1 (1) 3 (2) 0.93
invasive bacterial Children with cancer and high-risk FN require immediate hos-
infection, n (%) pitalization and aggressive intravenous antimicrobial treatment.
Re-instalment of 4 (5) 4 (2) We observed an uneventful resolution in 96% of all randomized FN
antimicrobials, n (%) episodes, despite the fact that 50% of them were classified as high
Development of sepsis, n (%) 1 (1) 0 1 (1)
risk at admission. Considering these data, systematic evaluation for
Admission to PICU, n (%) 1 (1) 0 1 (1)
Death, n (%) 0 0 0 respiratory viruses at the time of hospital admission could be
helpful to establish a more rational treatment in a selected group of
Abbreviations: AMC, absolute monocyte count; ANC, absolute neutrophil count;
IQR: Interquartile range; PICU, paediatric intensive care unit. patients. Miedema et al. [18] recently reported that it is safe to
shorten antimicrobial treatment to 72 h in selected medium-risk
children with FN; antimicrobials were stopped in 50 episodes and
Table 3 no failures were observed, however, no high-risk episodes were
Respiratory viruses identified in 176 children with episodes of fever and neu- included in this study.
tropenia, according to intervention
Approximately 79% of episodes of FN do not present a serious
c
Respiratory viruses Type of intervention Total bacterial infection [28], therefore a more extensive assessment
Maintain Antimicrobial with multiplex blood and respiratory PCR assays could increase
a
antimicrobial withholding b pathogen detection [6,24,29], facilitating a tailor-made therapy and
n ¼ 92 n ¼ 84 reducing unnecessary antimicrobial exposure [3].
This study had limitations, including that the intervention was
Rhinovirus 49 (53) 42 (50) 91 (41)
Respiratory sincytial virus 17 (19) 24 (29) 41 (19) not double blind. We decided not to conduct a double-blind study
Parainfluenza virus 21 (23) 18 (21) 39 (18) because the majority of these children received antimicrobial
Influenza virus 14 (15) 8 (10) 22 (10) therapy using their central venous catheter. We preferred not to use
Metapneumovirus 4 (4) 5 (6) 9 (4) the central venous catheter in children with antimicrobials with-
Adenovirus 5 (5) 2 (2) 7 (3)
held to avoid unnecessary manipulations. Another possible issue is
Bocavirus 5 (5) 5 (6) 10 (5)
Coronavirus 1 (1) 1 (1) 2 (1) that not all children randomized in this cohort with respiratory
a virus detection presented an upper or lower respiratory tract
Twenty-three episodes with viral co-infection. Twenty-one cases with two
respiratory viruses and two cases with three respiratory viruses. infection at the time of admission. Although positive PCR detection
b
Twenty-two episodes with viral co-infecction. All cases with two respiratory is not always necessarily related with respiratory disease [30], the
viruses. majority of children in this study (75%) presented respiratory
c
Without significant differences between groups. symptoms, suggesting a role for the respiratory viruses detected by
PCR.
In conclusion, we suggest incorporating molecular respiratory
observed between groups. These four viruses represented 88% of
viral study in the initial evaluation of all children with cancer and
the identified respiratory viruses in both groups. We detected 23
episodes of FN. The reduction of antimicrobial use in children with
and 22 cases of viral co-infection in each group. In 43/45 cases
FN with a demonstrated respiratory viral infection, based on
(96%) viral co-infection included two respiratory viruses. Three of
stringent clinical and microbiological/ molecular diagnostic criteria,
the four children requiring antimicrobial re-instalment had RSV
could favour the adoption of evidence-based and more rational
and one of them had a rhinovirus. The child that developed a
management strategies in this population.
Klebsiella pneumoniae sepsis had a positive parainfluenza virus
detection.
Transparency declaration
Discussion
The authors declare that they have no conflicts of interest.
Respiratory viruses were detected as sole pathogens in one-
third of children with cancer admitted because of a febrile neu- Funding
tropenic episode, of which almost half met study criteria for
favourable evolution at 48 h, allowing their randomization. Overall, This work was supported by the National Fund for Scientific and
95% of the episodes in which antimicrobials were withdrawn had Technological Development (FONDECYT), Chile (grants numbers
an uneventful resolution. 1120800, 1130911).
178 M.E. Santolaya et al. / Clinical Microbiology and Infection 23 (2017) 173e178

Acknowledgements private physician office settings in five communities of the state of Veracruz,
Mexico. BMC Res Notes 2015;8:261.
[16] Santolaya ME, Alvarez AM, Becker A, Cofre J, Enriquez N, O'Ryan M, et al.
We thank research nurses of the participant hospitals for their Prospective, multicenter evaluation of risk factors associated with invasive
invaluable support in enrolling patients and obtaining blood and bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol
nasopharyngeal samples. We appreciate the support provided by 2001;19:3415e21.
[17] Santolaya ME, Alvarez AM, Aviles CL, Becker A, Cofre J, Enriquez N, et al.
Magdalena Castro, RN and clinical epidemiologist in the statistical Prospective evaluation of a model of prediction of invasive bacterial infection
analysis. We thank the FONDECYT Programme for their support. risk among children with cancer, fever, and neutropenia. Clin Infect Dis
2002;35:678e83.
[18] Miedema KG, Tissing WJ, Abbink FC, Ball LM, Michiels EM, van Vliet MJ, et al.
References Risk-adapted approach for fever and neutropenia in paediatric cancer
patientsda national multicentre study. Eur J Cancer 2016;53:16e24.
[1] Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, et al. [19] Spasova MI, Grudeva-Popova JG, Kostyanev SS, Genev ED, Stoyanova AA,
Guideline for the management of fever and neutropenia in children with Kirina VI, et al. Risk index score for bacteremia in febrile neutropenic episodes
cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin in children with malignancies. J BUON 2009;14:411e8.
Oncol 2012;30:4427e38. [20] Villarroel M, Aviles CL, Silva P, Guzman AM, Poggi H, Alvarez AM, et al. Risk
[2] Hagag AA, Hassan SM, Elgamasy MA, Afifi IK. Study of Common Bacterial and factors associated with invasive fungal disease in children with cancer and
Fungal Pathogens in Children with Hematological Malignancies during Febrile febrile neutropenia: a prospective multicenter evaluation. Pediatr Infect Dis J
Neutropenia: Single Center Egyptian Study. Infect Disord Drug Targets 2010;29:816e21.
2016;16:54e62. [21] Ozsevik SN, Sensoy G, Karli A, Albayrak C, Dagdemir A, Belet N, et al. Invasive
[3] Barton CD, Waugh LK, Nielsen MJ, Paulus S. Febrile neutropenia in children fungal infections in children with hematologic and malignant diseases. J
treated for malignancy. J Infect 2015;71(Suppl. 1):S27e35. Pediatr Hematol Oncol 2015;37:e69e72.
[4] Santolaya ME. Supportive care in children. Curr Opin Oncol 2010;22:323e9. [22] Santolaya ME, Alvarez AM, Aviles CL, Becker A, Venegas M, ORyan  M, et al.
[5] Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 Prospective validation of a risk prediction model for severe sepsis in children
guidelines for the use of antimicrobial agents in neutropenic patients with with cancer and high risk fever and neutropenia. Pediatr Infect Dis J 2013;32:
cancer. Clin Infect Dis 2002;34:730e51. 1318e23.
[6] Torres JP, Labrana Y, Ibanez C, Kasaneva P, Farfan MJ, De la Maza V, et al. [23] Rondinelli PI, Ribeiro Kde C, de Camargo B. A proposed score for predicting
Frequency and clinical outcome of respiratory viral infections and mixed viral- severe infection complications in children with chemotherapy-induced febrile
bacterial infections in children with cancer, fever and neutropenia. Pediatr neutropenia. J Pediatr Hematol Oncol 2006;28:665e70.
Infect Dis J 2012;31:889e93. [24] Santolaya ME, Farfan MJ, De La Maza V, Cocina M, Santelices F, Alvarez AM,
[7] Benites EC, Cabrini DP, Silva AC, Silva JC, Catalan DT, Berezin EN, et al. Acute et al. Diagnosis of bacteremia in febrile neutropenic episodes in children with
respiratory viral infections in pediatric cancer patients undergoing chemo- cancer: microbiologic and molecular approach. Pediatr Infect Dis J 2011;30:
therapy. J Pediatr (Rio J) 2014;90:370e6. 957e61.
[8] Fukutani KF, Nascimento-Carvalho CM, Van der Gucht W, Wollants E, [25] Shachor-Meyouhas Y, Sprecher H, Moscoviz D, Zaidman I, Haimi M, Kassis I.
Khouri R, Dierckx T, et al. Pathogen transcriptional profile in nasopharyngeal Molecular-based diagnosis of bacteremia in the setting of fever with or
aspirates of children with acute respiratory tract infection. J Clin Virol without neutropenia in pediatric hematology-oncology patients. J Pediatr
2015;69:190e6. Hematol Oncol 2013;35:500e3.
[9] Meissner HC. Viral Bronchiolitis in Children. N Engl J Med 2016;374:62e72. [26] Santolaya ME, Alvarez AM, Aviles CL, Becker A, Cofre J, Cumsille MA, et al.
[10] Christensen MS, Nielsen LP, Hasle H. Few but severe viral infections in chil- Early hospital discharge followed by outpatient management versus
dren with cancer: a prospective RT-PCR and PCR-based 12-month study. continued hospitalization of children with cancer, fever, and neutropenia at
Pediatr Blood Cancer 2005;45:945e51. low risk for invasive bacterial infection. J Clin Oncol 2004;22:3784e9.
[11] Koskenvuo M, Mottonen M, Rahiala J, Saarinen-Pihkala UM, Riikonen P, [27] Paganini H, Santolaya ME, Alvarez M, Aran ~ a M, Arteaga R, Bonilla A, et al.
Waris M, et al. Respiratory viral infections in children with leukemia. Pediatr Diagno stico y tratamiento de la neutropenia febril en nin ~ os con ca ncer:
Infect Dis J 2008;27:974e80. Consenso de la Sociedad Latinoamericana de Infectología Pedi atrica. Rev chil
[12] Lindblom A, Bhadri V, Soderhall S, Ohrmalm L, Wong M, Norbeck O, et al. infectol 2011;28(Suppl. 1):10e38.
Respiratory viruses, a common microbiological finding in neutropenic chil- [28] Castagnola E, Fontana V, Caviglia I, Caruso S, Faraci M, Fioredda F, et al. A
dren with fever. J Clin Virol 2010;47:234e7. prospective study on the epidemiology of febrile episodes during chemo-
[13] Mendoza Sanchez MC, Ruiz-Contreras J, Vivanco JL, Fernandez-Carrion F, Baro therapy-induced neutropenia in children with cancer or after hemopoietic
Fernandez M, Ramos JT, et al. Respiratory virus infections in children with stem cell transplantation. Clin Infect Dis 2007;45:1296e304.
cancer or HIV infection. J Pediatr Hematol Oncol 2006;28:154e9. [29] Babady NE, Mead P, Stiles J, Brennan C, Li H, Shuptar S, et al. Comparison of the
[14] Martinez P, Cordero J, Valverde C, Unanue N, Dalmazzo R, Piemonte P, et al. Luminex xTAG RVP Fast assay and the Idaho Technology FilmArray RP assay
Viral respiratory co-infections in pediatric patients admitted for acute respi- for detection of respiratory viruses in pediatric patients at a cancer hospital. J
ratory infection and their impact on clinical severity. Rev Chilena Infectol Clin Microbiol 2012;50:2282e8.
2012;29:169e74. [30] Jartti T, Lehtinen P, Vuorinen T, Koskenvuo M, Ruuskanen O. Persistence of
[15] Wong-Chew RM, Espinoza MA, Taboada B, Aponte FE, Arias-Ortiz MA, Monge- rhinovirus and enterovirus RNA after acute respiratory illness in children. J
Martinez J, et al. Prevalence of respiratory virus in symptomatic children in Med Virol 2004;72:695e9.