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Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial
Accepted Manuscript Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial María E. Santolaya, Ana M. Alvarez, Mirta Acuña, Carmen L. Avilés, Carmen Salgado, Juan Tordecilla, Mónica Varas, Marcela Venegas, Milena Villarroel, Marcela Zubieta, Alberto Toso, Alexander Bataszew, Mauricio J. Farfán, Verónica de la Maza, Alejandra Vergara, Romina Valenzuela, Dr Juan P. Torres, MD, PhD PII:
S1198-743X(16)30556-0
DOI:
10.1016/j.cmi.2016.11.001
Reference:
CMI 769
To appear in:
Clinical Microbiology and Infection
Received Date: 17 August 2016 Revised Date:
3 November 2016
Accepted Date: 4 November 2016
Please cite this article as: Santolaya ME, Alvarez AM, Acuña M, Avilés CL, Salgado C, Tordecilla J, Varas M, Venegas M, Villarroel M, Zubieta M, Toso A, Bataszew A, Farfán MJ, Maza Vdl, Vergara A, Valenzuela R, Torres JP, Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial, Clinical Microbiology and Infection (2016), doi: 10.1016/j.cmi.2016.11.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Efficacy and safety of withholding antimicrobial treatment in children with cancer,
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fever and neutropenia, with a demonstrated viral respiratory infection: a randomized
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clinical trial.
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María E. Santolaya1,7, Ana M. Alvarez3,7, Mirta Acuña4,7, Carmen L. Avilés5,7, Carmen
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Salgado6,7, Juan Tordecilla4,7, Mónica Varas3,7, Marcela Venegas3, Milena Villarroel1,7,
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Marcela Zubieta6,7, Alberto Toso1, Alexander Bataszew1, Mauricio J. Farfán1, Verónica de
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la Maza1 , Alejandra Vergara2, Romina Valenzuela1 and Juan P. Torres1.
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Mackenna, Faculty of Medicine, Universidad de Chile; 3Department of Pediatrics, Hospital
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Department of Pediatrics and 2Center for Molecular Studies, Hospital Dr. Luis Calvo
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San Juan de Dios, Faculty of Medicine, Universidad de Chile; 4Department of Pediatrics,
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Hospital Dr. Roberto del Río, Faculty of Medicine, Universidad de Chile;5Department of
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Pediatrics, Hospital San Borja Arriarán, Faculty of Medicine, Universidad de Chile;
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Infectious Diseases, National Child Program of Antineoplastic Drugs Network, Santiago,
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Chile
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Running head: Antimicrobial withdrawal in children with fever and neutropenia
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Lenght of the abstract: 249 words
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Lenght of the paper: 3063 words
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Department of Pediatrics, Hospital Dr. Exequiel González Cortés;7Committee of
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Corresponding Author's Contact Information:
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Dr Juan Pablo Torres, MD, PhD
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Division of Pediatric Infectious Diseases
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Department of Pediatrics 1
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Faculty of Medicine, University of Chile
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Hospital Luis Calvo Mackenna
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Antonio Varas 360, Providencia
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Santiago, Chile
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Phone: 56-22-2362075
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Fax: 56-22-2362075
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E-mail: [email protected]
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Abstract
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Objectives. To determine efficacy and safety of withholding antimicrobials in children
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with cancer, fever and neutropenia (FN) with a demonstrated respiratory viral infection.
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Methods. Prospective, multicenter, randomized study in children presenting with FN at
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five hospitals in Santiago, Chile, evaluated at admission for diagnosis of bacterial and viral
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pathogens including PCR-microarray for 17 respiratory viruses. Children positive for a
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respiratory virus, negative for a bacterial pathogen and with a favorable evolution after 48
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hours of antimicrobial therapy were randomized to either maintain or withhold
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antimicrobials. Primary endpoint was percentage of episodes with uneventful resolution.
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Secondary endpoints were days of fever/hospitalization, bacterial infection, sepsis,
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admission to intensive care unit (PICU) and death.
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Results. A total of 319/ 951 children with FN episodes recruited between July 2012-
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December 2015 had a respiratory virus as a unique identified microorganism, of which
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176/319 were randomized, 92/176 to maintain antimicrobials and 84/176 to withdraw.
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Median days of antimicrobials use was 7 days (7-9) vs 3 (3-4), with similar frequency of
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uneventful resolution (89/92 (97%) and 80/84 (95%) respectively, P=NS, OR 1.48. (95%
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C.I. 0.32-6.83), P=0.61), similar number of days of fever (2 vs 1), days of hospitalization
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(6 vs 6) and bacterial infections throughout the episode (2%-1%), with one case of sepsis
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requiring PICU in the group that maintain antimicrobials, without cases of death.
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Conclusions. The reduction of antimicrobials in children with FN and respiratory viral
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infections, based on clinical and microbiological/molecular diagnostic criteria should favor
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the adoption of evidence-based management strategies in this population.
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Introduction
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Children with cancer are exposed to viral, bacterial and fungal infections, especially during
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the episodes of fever and neutropenia (FN)1-3. Episodes of FN during chemotherapy are
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currently managed within the hospital and with broad-spectrum antimicrobial therapy4,5.
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Until recently, the most common etiological agents reported in FN episodes occurring in
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children with cancer have been bacterial and fungal pathogens. Viral infections, particularly
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respiratory viruses, have been increasingly recognized as significant etiologic agents of FN
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in this population6,7
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Respiratory viral infections are a leading cause of morbidity and mortality in
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immunocompetent children 8,9. In pediatric patients with cancer, respiratory viruses can be
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detected in up to 57% of episodes of FN 6,7,10-13,14,15. In a previous study we determined the
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frequency and clinical outcome of respiratory virus-positive FN episodes. 6. Respiratory
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viruses were the most common agent detected and clinical outcomes of these episodes were
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significantly better than episodes with single bacterial infections or viral-bacterial co-
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infections. Children with respiratory viral infections had fewer days of hospitalization, a
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lower probability of hemodynamic instability and lower rates of admission to Pediatric
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Intensive Care Unit (PICU)6.
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For children with FN most research efforts have focused on management of bacterial and
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fungal infections, mainly in proposing models of risk prediction for invasive bacterial and
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fungal infections16-23, improvements in the molecular diagnosis of infections,24,25and
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selective antimicrobial management in children with high and low risk FN episodes18,26. In
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contrast with the increase in studies of bacterial and fungal infections in this population,
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studies of viral infections are scarce and have been recognized as a research gap in the
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field1. A rational approach towards the management of a potential infection in children with
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cancer and FN requires a comprehensive analysis of all microbiological agents involved.
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Implementation of a systematic study and early detection of respiratory viral infection in
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children with cancer and FN might help to optimize their management by reducing
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hospitalization and antimicrobial use.
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In this study we aim to determine efficacy and safety of withholding antimicrobial
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treatment 48 hours after admission in children with cancer and FN, with a demonstrated
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respiratory viral infection and a favourable clinical course.
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Patients and methods
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Population. From July, 2012 to December, 2015, a prospective, randomized, multicenter,
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government-sponsored study was conducted in five participating hospitals in Santiago,
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Chile, belonging to the National Child Program of Antineoplastic Drugs network. Children
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and adolescents with cancer < 18 years of age admitted by a FN episode were enrolled after
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parental and child signed informed consent and assent (if older than 8 years of age).
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Children with hematopoietic stem cell transplant were excluded. This study was approved
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by the Ethical Committee of each participating institution.
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Overall study design. Children were evaluated at admission in order to characterize the
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febrile episode, establish their risk for invasive bacterial infection and perform a common
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protocol for diagnosis of bacterial and viral pathogens. We recorded age, gender, type of
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cancer, type and date of the last chemotherapy, use of granulocyte - colony stimulating
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factors (G-CSF), use of antimicrobial prophylaxis, use of central venous catheter (CVC),
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hours of fever previous to admission, axillary temperature, blood pressure, heart rate,
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respiratory rate, signs and symptoms indicative of an infectious foci, especially respiratory
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signs/symptoms, haematological status (absolute neutrophil count (ANC), hemoglobin
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level, platelet count), biochemicaltests, quantitative C reactive protein (CRP), central and
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peripheral automated blood cultures, other cultures if clinically indicated, and a molecular-
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based evaluation for respiratory viruses.
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After initial evaluation, all children were treated following the Latin American Consensus
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for a Rational Approach of Children with FN27 and Guidelines for the management of FN
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in children with cancer 1. Briefly, children were hospitalized and low risk FN episodes were
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treated with a 3rd generation cephalosporin (ceftriaxone) while children at high risk were
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treated with an anti-pseudomonal 3rd generation cephalosporin (ceftazidim) plus amikacin
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with or without an anti Gram positive β lactamic or glycopeptides antimicrobial therapy.
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After 48 hours of hospitalization (day 3) children with a nasopharyngeal (NP) sample
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positive for a respiratory virus, absence of any positive bacterial culture and with a
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favourable clinical evolution, were subject to a 1:1 simple randomization by the study
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coordinator (blinded) using a statistical software (GraphPad Prism,version 6.01) into two
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groups: maintenance of antimicrobials until the end of the febrile episode, and the
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intervention group in which antimicrobials were withdrawn. According to Ethical
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Committee requirements, it was possible to randomize each child in only one episode of FN
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that met the study criteria, for this reason, one randomized episode of FN was equivalent to
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one randomized patient.
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Both groups were monitored daily for clinical and laboratory evolution until fever
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resolution and ANC ≥ 500/mm3.Children with a bacterial pathogen or children in whom all
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studies resulted negative continued their antimicrobial management according to current
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standard of care. In the antimicrobial withdraw group criteria for reinstallment
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antimicrobial therapy were: resurgence of fever, clinical worsening or new clinical and/or
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laboratory findings suggesting a bacterial infection. One blinded investigator evaluated all
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cases after discharge deciding that outcome was uneventful or not, without access to
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information about specific intervention of each child (see definitions).In children that
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continued with antimicrobial therapy, the standard duration of therapy was 7 days.
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Antimicrobial were stopped at day 7 if children had a favorable evolution, with at least a
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full day without fever and two consecutives CRP values equal or less that 40 mg/L. The
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ANC was not a criterion for stopping antimicrobial therapy.
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Study endpoints.The primary endpoint between the group that maintain antimicrobials and
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the group with antimicrobial withholding was i) number (%) of episodes with uneventful
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resolution. The secondary endpoints were i) number of days of fever, ii) number of days of
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hospitalization, iii) percentage of episodes that develop a demonstrated or probable
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invasive bacterial infection, iv) reinstallment of antimicrobial therapy, v) sepsis during
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hospitalization, vii) admission to the PICU, vii) death.
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Laboratory evaluation: Laboratory tests: hematological, biochemical and microbiogical tests were performed at each hospital according to standard techniques. 154
Molecular detection for respiratory viruses: Detection was performed on NP samples
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collected from all children at the time of admission (Copan™ flocked swabs, Brescia,
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Italy). The swab was inserted into a vial containing viral transport medium (UTM-RT,
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Copan™), transported to the central laboratory and stored at -80˚C until analysis in the next
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24 hours after admission. Total nucleic acid was extracted (easyMAG NucliSens;
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BioMérieux™, Durham, NC) and tested for 17 respiratory viruses (influenza A,B,C;
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parainfluenza1, 2, 3, 4a and 4b; RSV A and B; rhinovirus; adenovirus; echovirus; human
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bocavirus; coronavirus; human metapneumovirus A and B) by multiplex-polymerase chain
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reaction (PCR)-low density microarray, according to the manufacturer’s instructions
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(PneumoVir™;Genomica;Spain).
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Definitions: a) neutropenia: ANC ≤ 500/mm3; b) fever: single axillary Tº ≥ 38.5°C, or ≥
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38°C in two measurements separated by > 1 hour; c) high risk FN: A FN episode with one
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of the following factors at the time of admission: i) relapse of leukemia as cancer type, ii)
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hypotension or iii) quantitative CRP > than 90 mg/L, or with the following two factors: iv)
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< 7 days between the last chemotherapy and the beginning of the fever and v) platelet count
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< 50,000/mm3; d) low risk FN: A FN episode without the above mentioned factors, e)
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episodes with favorable evolution after 48 hours of antimicrobial therapy: good clinical
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condition(subjective evaluation of the clinical condition by the attending physician),
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temperature ≤ 38ºC, absence of an identifiable new clinical foci, and CRP < 90 mg/L; f)
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uneventful resolution: favorable resolution of the FN episode according to the randomized
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intervention, without changes in the therapy in the group that maintain antimicrobials and
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without reinstallment in the group with antimicrobial withholding; g)
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demonstrated/probable invasive bacterial infection: bacteremia or isolation of a bacteria
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from a normally sterile site, or clinical signs suggestive of a localized bacterial infection,
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with parenchymal involvement, with or without microbiological isolation; h) sepsis:
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systemic inflammatory response syndrome, accompanied by abnormal tissue perfusion,
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caused by a presumptive bacterial infection, with or without microbiological confirmation,
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i) respiratory viral infection: detection of ≥ 1 respiratory virus in NP sample by PCR; j)
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upper/lower respiratory viral infection: Infection of respiratory tract that clinically affects
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from the larynx toward proximal or beyond the larynx plus respiratory viral infection,
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respectively.
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Sample size and statistical analysis:
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Sample size. The primary endpoint for this non-inferiority study was i) number (%) of
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episodes with uneventful resolution. Sample size was calculated based on the hypothesis
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that the frequency of occurrence of uneventful resolution was the same for both groups.
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Considering an unfavourable outcome of 10% as previously reported for this population, a
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maximum acceptable difference of 10% between groups, a type I error of 0.05 and a
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potency of 90%, we calculated that 134 episodes were required, 67 in the group that
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maintain antimicrobial therapy and 67 in antimicrobial withholding group. The overall
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capacity of enrolment in the five study sites was estimated in 300 episodes per year
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(25/month). Our enrolment was estimated for a total of 1,000 FN episodes in the study
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period. Statistical analysis. Categorical variables were compared with Chi square test or
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Fisher exact test depending in the number of episodes per comparison group. Continuous
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variables were compared between the two groups according to their distribution(T-student
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or Mann Whitney test).The risk for an uneventfully resolution was evaluated between the
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exposed and non exposed groups calculating the odd ratio (OR) with the respective 95%
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confidence interval (C.I.). Statistical analyses were performed with the Sigma Stat 3.0
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Program and Systat Software, CA, USA.
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Results
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Population characteristics
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Between July 2012 and December 2015, a total of 1121 episodes of FN were evaluated in
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the five Hospitals participating in the study, of which 951 (85%) episodes were enrolled
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and 170/1121 (15%) were excluded, because 97/170 (57%) children and their parent
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refused to participate, 68/170 (40%) episodes did not meet the inclusion criteriaand 5/170
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(3%) had incomplete data. The 951 episodes enrolled were evaluated for bacterial and viral
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infections and all received empiric antimicrobial therapy. Three hundred and nineteen/951
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episodes (34%) had a positive NP sample for respiratory viruses at admission and were
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negative for a bacterial pathogen. Forty eight hours later, 176/319 (55%)of these episodes
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met all criteria for randomization, of which, 92/176 (52%) were randomized into a current
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antimicrobial management and 84/176 (48%) into antimicrobial withholding. At the time
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of randomization, median ANC was 132/mm3 and 207/mm3in the maintenance and
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withholding antimicrobial group, respectively (P=0.15), with 87% and 80% of children
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having an ANC ≤ 500/mm3 in each group (P=0.3).From 143 episodes positive for a
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respiratory virus and negative for a bacterial pathogen not randomized, 109 did not have a
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favorable evolution after 48 hours of antimicrobial therapy (104 maintain fever or CRP >
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90 mg/L, 5 had hemodynamic instability), 21 had new clinical foci and 13 were not
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randomized by no adherence to the protocol (Figure 1).
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Table 1 describes the main characteristics of children with episodes of FN and a positive
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respiratory viral infection randomized to both groups. Age, gender, type of cancer and other
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characteristics were similar between the two groups (P=NS). Less than 10% of children in
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each group received prophylaxis other than trimethoprim-sulfamethoxazole for
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Pneumocystis jiroveci. Eighty eight/176 episodes (50%) had a high risk FN. Of 176
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episodes randomized, 65/92 (71%) and 66/84 (78%) respectively had clinical
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characteristics suggesting an upper/lower respiratory tract infection at the time of
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admission.
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Outcome of children with febrile neutropenic episodes by study groups.
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Table 2 shows the outcome of 176 randomized children, according to intervention. As
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expected, median days of antimicrobial therapy was significantly different in children that
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maintained (7 days, IQR 7-9 days) compared to children in whom antimicrobials were
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withdrawn (3 days, IQR3-4 days), P<0.0001. Percentage of episodes of FN with uneventful
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resolution was 89/92 (97%) and 80/84 (95%) respectively (P=NS), OR 1.48. (95% C.I.
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0.32-6.83), P=0.61. Days of fever (2 and 1), days of hospitalization (6 and 6) and
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development of a demonstrated/probable invasive bacterial infection (2% and 1%) were
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similar among groups. No deaths occurred.
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Three children had a demonstrated/probable bacterial infection, two had bacteremia caused
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by ESBL (+) Klebsiella pneumoniae in the group maintaining antimicrobials and one case
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of a culture negative sinusitis in the antimicrobials withholding group. Reinstallment of
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antimicrobial therapy was indicated in 4 children. All 4 had acute myeloid leukemia, were
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admitted with a high risk FN and met study criteria for upper respiratory viral infection. In
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the 4 cases the antimicrobials were discontinued with children in good clinical conditions,
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temperature < 38°C and CRP < 90 mg/L, according to the protocol. Three of them
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presented with fever between days 5 and 7 after admission, without an identifiable new foci
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or clinical deterioration and with CRP < 90 mg/L. The clinical course was favorable in
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three of the children with fever declining after one day of new antimicrobial therapy, in
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absence of any bacterial pathogen detection. The fourth child developed fever on day 5 and
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an increase in CRP to 100 mg/L. Clinical and imaging findings suggested sinusitis
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requiring a 14 days of antimicrobial therapy. The child did not develop sepsis and was not
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admitted to PICU. He was discharged with a diagnosis of probable invasive bacterial
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infection.
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One child from the group that maintained antimicrobials developed sepsis and was admitted
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to the PICU. She was a 3 year old girl with a neuroblastoma, a high risk FN and an upper
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respiratory infection. At the day of randomization, she was afebrile and CRP value was 14
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mg/L. On day 6 she presented with fever and hemodynamic instability. Blood cultures
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obtained at day 6 were positive for an ESBL (+) Klebsiella pneumoniae, CRP value
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increased up to 250 mg/L and she was admitted to PICU receiving antimicrobials based on
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the bacterial isolation by a new period of 14 days, with good clinical outcome. No deaths
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occurred among the 176 randomized children through the study period.
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We performed a separated analysis of the 176 episodes randomized according to the risk
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status for invasive bacterial infection determined at admission. For the 88 children with
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episodes of low risk FN the median days of antimicrobial therapy was 7 days (IQR 7-9) and
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3 days (IQR 3-3), P<0.001; with 98 and 100% of episodes with uneventful resolution,
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without cases of antimicrobials reinstallment, development of sepsis and admission to
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PICU. In the 88 episodes of high risk FN, the median days of antimicrobial therapy was 7
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days (IQR 7-9) and 4 days (IQR 3-5), P<0.001, with 93% of episodes with uneventful
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resolution in both groups, with the 4 cases of antimicrobials reinstallment and 1 case of
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sepsis and admission to PICU, all of them described previously.
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Respiratory viruses identified in each study group
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The main respiratory viruses identified in the 176 children randomized with episodes of FN
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are described in Table 3. Overall, the most common respiratory virus was rhinovirus (41%)
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followed by RSV, parainfluenza and influenza virus with no differences observed between
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groups. These four viruses represented 88% of the identified respiratory viruses in both
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groups. We detected 23 and 22 cases of viral co-infection in each group. In 43/45 cases
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(96%) viral co-infection included two respiratory viruses. Three of the 4 children requiring
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antimicrobials reinstallment had RSV and one of them a rhinovirus. The child that
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developed a Klebsiella pneumonia sepsis had a positive parainfluenza virus detection.
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Discussion
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Respiratory viruses were detected as sole pathogens in one third of children with cancer
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admitted because of a febrile neutropenic episode of which near half met study criteria of a
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favorable evolution at 48 hours allowing their randomization. Overall, 95% of the episodes
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in which antimicrobials were withdrawn had an uneventful resolution.
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We previously demonstrated that it was possible to apply a selective management,
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proposing ambulatory therapy in children with low risk FN, defined according to the
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following parameters: type of cancer, hemodynamic stability, CRP values, platelet count
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and number of days since the last chemotherapy26. In this study, we advance a step further,
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including the possibility to stopped antimicrobial therapy after 48 hours of admission in
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children with a positive respiratory viral infection, a negative bacterial infection and a
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favorable clinical course, including episodes of low and high risk for invasive bacterial
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infection.
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Knowledge on the epidemiology of respiratory viral infection in immunocompromised
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children is scarce with few systematic studies aimed to determine their clinical impact6.
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RSV, influenza, parainfluenza, adenovirus and picornaviruses have been the most common
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etiologic agents detected in this population 6,7,12. The increasing detection of viruses
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highlights the relevance of optimizing viral diagnosis in children with FN 1.
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Children with cancer and high risk FN require immediate hospitalization and aggressive
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intravenous antimicrobial treatment. We observed an uneventful resolution in 96% of all
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randomized FN episodes, despite the fact that 50% of them were classified as high risk at
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admission. Considering these data, systematic evaluation for respiratory viruses at the time
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of hospital admission could be helpful to establish a more rational treatment in a selected
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group of patients. Miedema and cols.18 recently reported that it is safe to shorten
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antimicrobial treatment to 72 hours in selected medium-risk children withFN;
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antimicrobials were stopped in 50 episodes and no failures were observed, however, no
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high risk episodes were included in this study.
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Approximately 79% of episodes of FN do not present a serious bacterial infection 28,
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therefore a more extensive assessment with multiplex blood and respiratory PCR assays
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could increase pathogens detection6,24, 29, facilitating a tailor-made therapy and reducing
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unnecessary antimicrobial exposure3.
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This study had limitations, including that the intervention was not double blind. We
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decided not to conduct a double blind study because the majority of these children received
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antimicrobial therapy using their CVC. We preferred not to use the CVC in children with
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antimicrobials withholding in order to avoid not necessary manipulations. Another possible
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issue is that not all children randomized in this cohort with respiratory viruses detection
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presented an upper or lower respiratory tract infection at the time of admission. Although
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positive-PCR detection is not always necessarily related with respiratory disease30, the
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majority of children in this study (75%) presented respiratory symptoms, suggesting a role
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of the respiratory viruses detected by PCR.
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In conclusion, we suggest incorporating molecular respiratory viral study in the initial
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evaluation of all children with cancer and episodes of FN. The reduction of antimicrobial 323
use in children with FN with a demonstrated respiratory viral infection, based on stringent 324
clinical and microbiological/ molecular diagnostic criteria could favor the adoption of 325
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Funding
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This work was supported by the National Fund for Scientific and Technological
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Development (FONDECYT), Chile [grants numbers 1120800, 1130911].
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Acknowledgment 332
We thank research nurses of the participant hospitals for their invaluable support in enroll
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patients and obtain blood and nasopharyngeal samples. We appreciate the support provided
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by Magdalena Castro, RN and clinical epidemiologist in the statistical analysis. We thank
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FONDECYT Program for their support
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pediatric cancer patients undergoing chemotherapy. J Pediatr (Rio J) 90:370-6, 2014 8.
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transcriptional profile in nasopharyngeal aspirates of children with acute respiratory tract infection.
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Meissner HC: Viral Bronchiolitis in Children. N Engl J Med 374:62-72, 2016
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Christensen MS, Nielsen LP, Hasle H: Few but severe viral infections in children
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with cancer: a prospective RT-PCR and PCR-based 12-month study. Pediatr Blood Cancer 45:945-
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51, 2005
361 362
11.
Koskenvuo M, Mottonen M, Rahiala J, et al: Respiratory viral infections in children
with leukemia. Pediatr Infect Dis J 27:974-80, 2008 17
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microbiological finding in neutropenic children with fever. J Clin Virol 47:234-7, 2010 13.
365 366
Mendoza Sanchez MC, Ruiz-Contreras J, Vivanco JL, et al: Respiratory virus
infections in children with cancer or HIV infection. J Pediatr Hematol Oncol 28:154-9, 2006 14.
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Lindblom A, Bhadri V, Soderhall S, et al: Respiratory viruses, a common
Martinez P, Cordero J, Valverde C, et al: [Viral respiratory co-infections in
pediatric patients admitted for acute respiratory infection and their impact on clinical severity]. Rev
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Chilena Infectol 29:169-74, 2012 15.
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Wong-Chew RM, Espinoza MA, Taboada B, et al: Prevalence of respiratory virus
in symptomatic children in private physician office settings in five communities of the state of
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Veracruz, Mexico. BMC Res Notes 8:261, 2015 16.
373
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Santolaya ME, Alvarez AM, Becker A, et al: Prospective, multicenter evaluation of
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risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and
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fever. J Clin Oncol 19:3415-21, 2001
Santolaya ME, Alvarez AM, Aviles CL, et al: Prospective evaluation of a model of
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prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia.
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Clin Infect Dis 35:678-83, 2002
Miedema KG, Tissing WJ, Abbink FC, et al: Risk-adapted approach for fever and
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neutropenia in paediatric cancer patients - A national multicentre study. Eur J Cancer 53:16-24,
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382 383 384
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19.
Spasova MI, Grudeva-Popova JG, Kostyanev SS, et al: Risk index score for
bacteremia in febrile neutropenic episodes in children with malignancies. J BUON 14:411-8, 2009 20.
Villarroel M, Aviles CL, Silva P, et al: Risk factors associated with invasive fungal
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disease in children with cancer and febrile neutropenia: a prospective multicenter evaluation.
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Pediatr Infect Dis J 29:816-21, 2010
387 388
21.
Ozsevik SN, Sensoy G, Karli A, et al: Invasive fungal infections in children with
hematologic and malignant diseases. J Pediatr Hematol Oncol 37:e69-72, 2015 18
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22.
Santolaya ME, Alvarez AM, Aviles CL, et al: Prospective Validation of a Risk
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Prediction Model for Severe Sepsis in Children with Cancer and High Risk Fever and Neutropenia.
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Pediatr Infect Dis J, 2013 23.
Rondinelli PI, Ribeiro Kde C, de Camargo B: A proposed score for predicting
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severe infection complications in children with chemotherapy-induced febrile neutropenia. J Pediatr
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Hematol Oncol 28:665-70, 2006 24.
Santolaya ME, Farfan MJ, De La Maza V, et al: Diagnosis of bacteremia in febrile
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neutropenic episodes in children with cancer: microbiologic and molecular approach. Pediatr Infect
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Dis J 30:957-61, 2011
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25.
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Shachor-Meyouhas Y, Sprecher H, Moscoviz D, et al: Molecular-based diagnosis
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of bacteremia in the setting of fever with or without neutropenia in pediatric hematology-oncology
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patients. J Pediatr Hematol Oncol 35:500-3, 2013
401
26.
Santolaya ME, Alvarez AM, Aviles CL, et al: Early hospital discharge followed by
outpatient management versus continued hospitalization of children with cancer, fever, and
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neutropenia at low risk for invasive bacterial infection. J Clin Oncol 22:3784-9, 2004
404
27.
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Paganini H, Santolaya ME, Alvarez M, et al. Diagnóstico y tratamiento de la
neutropenia febril en niños con cáncer: Consenso de la Sociedad Latinoamericana de Infectología
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Pediátrica. Rev chil infectol 28: suppl.1, 10-38, 2011 28.
Castagnola E, Fontana V, Caviglia I, et al: A prospective study on the epidemiology
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of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after
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hemopoietic stem cell transplantation. Clin Infect Dis 45:1296-304, 2007
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29.
Babady NE, Mead P, Stiles J, et al: Comparison of the Luminex xTAG RVP Fast
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assay and the Idaho Technology FilmArray RP assay for detection of respiratory viruses in pediatric
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patients at a cancer hospital. J Clin Microbiol 50:2282-8, 2012
413 414
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Jartti T, Lehtinen P, Vuorinen T, et al: Persistence of rhinovirus and enterovirus
RNA after acute respiratory illness in children. J Med Virol 72:695-9, 2004 19
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Legends of Tables and Figures
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Figure 1. Episodes of fever and neutropenia evaluated, enrolled and randomized during
417
study period
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Table 1. Admission characteristics of 176 episodes of fever and neutropenia in children
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with a demonstrated respiratory viral infection, according to intervention
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Table 2. Outcome of 176 children with fever, neutropenia and a demonstrated respiratory
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viral infection, according to intervention
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Table 3. Respiratory viruses identified in 176 children with episodes of fever and
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neutropenia, according to intervention
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Type of Intervention
5 (3-9) 40 (44)
4 (3-8) 46 (55)
0.57 0.13
49 (53) 7 (8) 36 (39) 43 (47) 27 (29) 77 (84) 2 (1-4)
55 (66) 4 (5) 25 (29) 45 (54) 26 (31) 68 (81) 2 (1-3)
0.09 0.43 0.19 0.36 0.81 0.63 0.10
13 (16) 44 (52) 22 (26) 5 (6) 0
0.37 0.37 0.85 0.87
19 (20) 42 (46) 23 (25) 6 (7) 2 (2)
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Antimicrobial withholding N = 84
Age in years, median (IQR) Male gender, n (%) Type of cancer, n (%) Leukemia/Lymphoma Leukemia relapse Solid tumors High risk for invasive bacterial infection, n (%) Use of G-CSF, n (%) Use of CVC, n (%) Hours of fever previous to admission, median (IQR) Admission clinical diagnosis, n (% ) Fever without focus Upper respiratory infection Lower respiratory infection Intestinal focus Others†
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G-CSF: granulocyte-colony stimulating factor; CVC: central venous catheter; IQR: Interquartile range *None of the characteristic differences between groups were significant † Others: Skin/soft tissue infection
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Maintain Antimicrobial N =92
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Characteristics
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Type of intervention
Days of antimicrobial therapy, median (IQR) Days of fever after admission, median (IQR) Days of hospitalization, median (IQR) Days of ANC < 500/mm3, median (IQR) Days of AMC < 100/mm3, median (IQR) Resolving uneventfully, n (%) Demonstrated/probable invasive bacterial infection, n (%) Reinstallment of antimicrobials, n (%) Development of sepsis, n (%) Admission to PICU, n (%) Death, n (%)
Total
Maintain Antimicrobial N =92
Antimicrobial Withholding N = 84
7 (7-9) 2 (1-3) 6 (4-8) 5 (3-8) 3 (0-6) 89 (97) 2 (2)
3 (3-4) 1 (1-2) 6 (4-7) 4 (3-8) 2 (0-5) 80 (95) 1 (1) 4 (5) 0 0 0
1 (1) 1 (1) 0
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ANC: absolute neutrophil count; AMC, absolute monocyte count; PICU, pediatric intensive care unit; IQR: Interquartile range
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6 (3-7) 1 (1-2) 6 (4-7) 5 (3-8) 3 (0-5) 169 (96) 3 (2) 4 (2) 1 (1) 1 (1) 0
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< 0.0001 0.44 0.65 0.23 0.46 0.61 0.93
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Type of intervention Maintain Antimicrobial * N=92
Antimicrobial Withholding † N = 84
Total ‡
49 (53) 17 (19) 21 (23) 14 (15) 4 (4) 5 (5) 5 (5) 1 (1)
42 (50) 24 (29) 18 (21) 8 (10) 5 (6) 2 (2) 5 (6) 1 (1)
91 (41) 41 (19) 39 (18) 22 (10) 9 (4) 7 (3) 10 (5) 2 (1)
Rhinovirus Respiratory sincytial virus Parainfluenza Influenza Metapneumovirus Adenovirus Bocavirus Coronavirus
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* 23 episodes with viral co-infection. Twenty one cases with 2 respiratory viruses and 2 cases with 3 respiratory viruses † 22 episodes with viral co-infecction All cases with 2 respiratory viruses ‡ Without significant differences between groups
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Respiratory viruses
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Febrile Neutropenia Episodes (n=1121)
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170 episodes excluded: - 97 reject informed consent - 68 not meet inclusion criteria - 5 incomplete data
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Enrolled Episodes (n=951)
No pathogen detected (n=356)
Respiratory Virus (+) Bacteria (-) (n=319)
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Randomized Episodes (n=176)
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Maintain antimicrobial therapy (n=92)
Respiratory Virus (+) Bacteria (+) (n=122)
143 episodes excluded: - 109 Unfavorable evolution (fever, CRP ≥90mg/L, hemodynamic instability) - 21 New clinical foci - 13 No adherence to protocol criteria
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Respiratory Virus (-) Bacteria (+) (n=154)
Withhold antimicrobial therapy (n=84)
S1198-743X(16)30556-0
DOI:
10.1016/j.cmi.2016.11.001
Reference:
CMI 769
To appear in:
Clinical Microbiology and Infection
Received Date: 17 August 2016 Revised Date:
3 November 2016
Accepted Date: 4 November 2016
Please cite this article as: Santolaya ME, Alvarez AM, Acuña M, Avilés CL, Salgado C, Tordecilla J, Varas M, Venegas M, Villarroel M, Zubieta M, Toso A, Bataszew A, Farfán MJ, Maza Vdl, Vergara A, Valenzuela R, Torres JP, Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial, Clinical Microbiology and Infection (2016), doi: 10.1016/j.cmi.2016.11.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Efficacy and safety of withholding antimicrobial treatment in children with cancer,
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fever and neutropenia, with a demonstrated viral respiratory infection: a randomized
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clinical trial.
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María E. Santolaya1,7, Ana M. Alvarez3,7, Mirta Acuña4,7, Carmen L. Avilés5,7, Carmen
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Salgado6,7, Juan Tordecilla4,7, Mónica Varas3,7, Marcela Venegas3, Milena Villarroel1,7,
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Marcela Zubieta6,7, Alberto Toso1, Alexander Bataszew1, Mauricio J. Farfán1, Verónica de
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la Maza1 , Alejandra Vergara2, Romina Valenzuela1 and Juan P. Torres1.
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1
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Mackenna, Faculty of Medicine, Universidad de Chile; 3Department of Pediatrics, Hospital
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Department of Pediatrics and 2Center for Molecular Studies, Hospital Dr. Luis Calvo
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San Juan de Dios, Faculty of Medicine, Universidad de Chile; 4Department of Pediatrics,
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Hospital Dr. Roberto del Río, Faculty of Medicine, Universidad de Chile;5Department of
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Pediatrics, Hospital San Borja Arriarán, Faculty of Medicine, Universidad de Chile;
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6
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Infectious Diseases, National Child Program of Antineoplastic Drugs Network, Santiago,
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Chile
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Running head: Antimicrobial withdrawal in children with fever and neutropenia
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Lenght of the abstract: 249 words
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Lenght of the paper: 3063 words
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Department of Pediatrics, Hospital Dr. Exequiel González Cortés;7Committee of
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Corresponding Author's Contact Information:
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Dr Juan Pablo Torres, MD, PhD
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Division of Pediatric Infectious Diseases
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Department of Pediatrics 1
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Faculty of Medicine, University of Chile
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Hospital Luis Calvo Mackenna
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Antonio Varas 360, Providencia
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Santiago, Chile
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Phone: 56-22-2362075
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Fax: 56-22-2362075
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E-mail: [email protected]
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Abstract
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Objectives. To determine efficacy and safety of withholding antimicrobials in children
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with cancer, fever and neutropenia (FN) with a demonstrated respiratory viral infection.
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Methods. Prospective, multicenter, randomized study in children presenting with FN at
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five hospitals in Santiago, Chile, evaluated at admission for diagnosis of bacterial and viral
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pathogens including PCR-microarray for 17 respiratory viruses. Children positive for a
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respiratory virus, negative for a bacterial pathogen and with a favorable evolution after 48
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hours of antimicrobial therapy were randomized to either maintain or withhold
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antimicrobials. Primary endpoint was percentage of episodes with uneventful resolution.
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Secondary endpoints were days of fever/hospitalization, bacterial infection, sepsis,
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admission to intensive care unit (PICU) and death.
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Results. A total of 319/ 951 children with FN episodes recruited between July 2012-
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December 2015 had a respiratory virus as a unique identified microorganism, of which
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176/319 were randomized, 92/176 to maintain antimicrobials and 84/176 to withdraw.
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Median days of antimicrobials use was 7 days (7-9) vs 3 (3-4), with similar frequency of
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uneventful resolution (89/92 (97%) and 80/84 (95%) respectively, P=NS, OR 1.48. (95%
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C.I. 0.32-6.83), P=0.61), similar number of days of fever (2 vs 1), days of hospitalization
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(6 vs 6) and bacterial infections throughout the episode (2%-1%), with one case of sepsis
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requiring PICU in the group that maintain antimicrobials, without cases of death.
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Conclusions. The reduction of antimicrobials in children with FN and respiratory viral
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infections, based on clinical and microbiological/molecular diagnostic criteria should favor
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the adoption of evidence-based management strategies in this population.
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Introduction
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Children with cancer are exposed to viral, bacterial and fungal infections, especially during
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the episodes of fever and neutropenia (FN)1-3. Episodes of FN during chemotherapy are
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currently managed within the hospital and with broad-spectrum antimicrobial therapy4,5.
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Until recently, the most common etiological agents reported in FN episodes occurring in
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children with cancer have been bacterial and fungal pathogens. Viral infections, particularly
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respiratory viruses, have been increasingly recognized as significant etiologic agents of FN
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in this population6,7
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Respiratory viral infections are a leading cause of morbidity and mortality in
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immunocompetent children 8,9. In pediatric patients with cancer, respiratory viruses can be
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detected in up to 57% of episodes of FN 6,7,10-13,14,15. In a previous study we determined the
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frequency and clinical outcome of respiratory virus-positive FN episodes. 6. Respiratory
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viruses were the most common agent detected and clinical outcomes of these episodes were
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significantly better than episodes with single bacterial infections or viral-bacterial co-
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infections. Children with respiratory viral infections had fewer days of hospitalization, a
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lower probability of hemodynamic instability and lower rates of admission to Pediatric
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Intensive Care Unit (PICU)6.
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For children with FN most research efforts have focused on management of bacterial and
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fungal infections, mainly in proposing models of risk prediction for invasive bacterial and
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fungal infections16-23, improvements in the molecular diagnosis of infections,24,25and
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selective antimicrobial management in children with high and low risk FN episodes18,26. In
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contrast with the increase in studies of bacterial and fungal infections in this population,
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studies of viral infections are scarce and have been recognized as a research gap in the
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field1. A rational approach towards the management of a potential infection in children with
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cancer and FN requires a comprehensive analysis of all microbiological agents involved.
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Implementation of a systematic study and early detection of respiratory viral infection in
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children with cancer and FN might help to optimize their management by reducing
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hospitalization and antimicrobial use.
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In this study we aim to determine efficacy and safety of withholding antimicrobial
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treatment 48 hours after admission in children with cancer and FN, with a demonstrated
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respiratory viral infection and a favourable clinical course.
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Patients and methods
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Population. From July, 2012 to December, 2015, a prospective, randomized, multicenter,
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government-sponsored study was conducted in five participating hospitals in Santiago,
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Chile, belonging to the National Child Program of Antineoplastic Drugs network. Children
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and adolescents with cancer < 18 years of age admitted by a FN episode were enrolled after
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parental and child signed informed consent and assent (if older than 8 years of age).
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Children with hematopoietic stem cell transplant were excluded. This study was approved
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by the Ethical Committee of each participating institution.
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Overall study design. Children were evaluated at admission in order to characterize the
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febrile episode, establish their risk for invasive bacterial infection and perform a common
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protocol for diagnosis of bacterial and viral pathogens. We recorded age, gender, type of
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cancer, type and date of the last chemotherapy, use of granulocyte - colony stimulating
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factors (G-CSF), use of antimicrobial prophylaxis, use of central venous catheter (CVC),
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hours of fever previous to admission, axillary temperature, blood pressure, heart rate,
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respiratory rate, signs and symptoms indicative of an infectious foci, especially respiratory
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signs/symptoms, haematological status (absolute neutrophil count (ANC), hemoglobin
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level, platelet count), biochemicaltests, quantitative C reactive protein (CRP), central and
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peripheral automated blood cultures, other cultures if clinically indicated, and a molecular-
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based evaluation for respiratory viruses.
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After initial evaluation, all children were treated following the Latin American Consensus
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for a Rational Approach of Children with FN27 and Guidelines for the management of FN
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in children with cancer 1. Briefly, children were hospitalized and low risk FN episodes were
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treated with a 3rd generation cephalosporin (ceftriaxone) while children at high risk were
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treated with an anti-pseudomonal 3rd generation cephalosporin (ceftazidim) plus amikacin
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with or without an anti Gram positive β lactamic or glycopeptides antimicrobial therapy.
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After 48 hours of hospitalization (day 3) children with a nasopharyngeal (NP) sample
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positive for a respiratory virus, absence of any positive bacterial culture and with a
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favourable clinical evolution, were subject to a 1:1 simple randomization by the study
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coordinator (blinded) using a statistical software (GraphPad Prism,version 6.01) into two
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groups: maintenance of antimicrobials until the end of the febrile episode, and the
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intervention group in which antimicrobials were withdrawn. According to Ethical
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Committee requirements, it was possible to randomize each child in only one episode of FN
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that met the study criteria, for this reason, one randomized episode of FN was equivalent to
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one randomized patient.
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Both groups were monitored daily for clinical and laboratory evolution until fever
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resolution and ANC ≥ 500/mm3.Children with a bacterial pathogen or children in whom all
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studies resulted negative continued their antimicrobial management according to current
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standard of care. In the antimicrobial withdraw group criteria for reinstallment
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antimicrobial therapy were: resurgence of fever, clinical worsening or new clinical and/or
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laboratory findings suggesting a bacterial infection. One blinded investigator evaluated all
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cases after discharge deciding that outcome was uneventful or not, without access to
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information about specific intervention of each child (see definitions).In children that
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continued with antimicrobial therapy, the standard duration of therapy was 7 days.
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Antimicrobial were stopped at day 7 if children had a favorable evolution, with at least a
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full day without fever and two consecutives CRP values equal or less that 40 mg/L. The
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ANC was not a criterion for stopping antimicrobial therapy.
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Study endpoints.The primary endpoint between the group that maintain antimicrobials and
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the group with antimicrobial withholding was i) number (%) of episodes with uneventful
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resolution. The secondary endpoints were i) number of days of fever, ii) number of days of
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hospitalization, iii) percentage of episodes that develop a demonstrated or probable
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invasive bacterial infection, iv) reinstallment of antimicrobial therapy, v) sepsis during
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hospitalization, vii) admission to the PICU, vii) death.
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Laboratory evaluation: Laboratory tests: hematological, biochemical and microbiogical tests were performed at each hospital according to standard techniques. 154
Molecular detection for respiratory viruses: Detection was performed on NP samples
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collected from all children at the time of admission (Copan™ flocked swabs, Brescia,
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Italy). The swab was inserted into a vial containing viral transport medium (UTM-RT,
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Copan™), transported to the central laboratory and stored at -80˚C until analysis in the next
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24 hours after admission. Total nucleic acid was extracted (easyMAG NucliSens;
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BioMérieux™, Durham, NC) and tested for 17 respiratory viruses (influenza A,B,C;
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parainfluenza1, 2, 3, 4a and 4b; RSV A and B; rhinovirus; adenovirus; echovirus; human
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bocavirus; coronavirus; human metapneumovirus A and B) by multiplex-polymerase chain
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reaction (PCR)-low density microarray, according to the manufacturer’s instructions
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(PneumoVir™;Genomica;Spain).
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Definitions: a) neutropenia: ANC ≤ 500/mm3; b) fever: single axillary Tº ≥ 38.5°C, or ≥
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38°C in two measurements separated by > 1 hour; c) high risk FN: A FN episode with one
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of the following factors at the time of admission: i) relapse of leukemia as cancer type, ii)
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hypotension or iii) quantitative CRP > than 90 mg/L, or with the following two factors: iv)
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< 7 days between the last chemotherapy and the beginning of the fever and v) platelet count
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< 50,000/mm3; d) low risk FN: A FN episode without the above mentioned factors, e)
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episodes with favorable evolution after 48 hours of antimicrobial therapy: good clinical
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condition(subjective evaluation of the clinical condition by the attending physician),
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temperature ≤ 38ºC, absence of an identifiable new clinical foci, and CRP < 90 mg/L; f)
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uneventful resolution: favorable resolution of the FN episode according to the randomized
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intervention, without changes in the therapy in the group that maintain antimicrobials and
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without reinstallment in the group with antimicrobial withholding; g)
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demonstrated/probable invasive bacterial infection: bacteremia or isolation of a bacteria
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from a normally sterile site, or clinical signs suggestive of a localized bacterial infection,
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with parenchymal involvement, with or without microbiological isolation; h) sepsis:
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systemic inflammatory response syndrome, accompanied by abnormal tissue perfusion,
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caused by a presumptive bacterial infection, with or without microbiological confirmation,
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i) respiratory viral infection: detection of ≥ 1 respiratory virus in NP sample by PCR; j)
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upper/lower respiratory viral infection: Infection of respiratory tract that clinically affects
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from the larynx toward proximal or beyond the larynx plus respiratory viral infection,
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respectively.
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Sample size and statistical analysis:
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Sample size. The primary endpoint for this non-inferiority study was i) number (%) of
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episodes with uneventful resolution. Sample size was calculated based on the hypothesis
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that the frequency of occurrence of uneventful resolution was the same for both groups.
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Considering an unfavourable outcome of 10% as previously reported for this population, a
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maximum acceptable difference of 10% between groups, a type I error of 0.05 and a
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potency of 90%, we calculated that 134 episodes were required, 67 in the group that
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maintain antimicrobial therapy and 67 in antimicrobial withholding group. The overall
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capacity of enrolment in the five study sites was estimated in 300 episodes per year
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(25/month). Our enrolment was estimated for a total of 1,000 FN episodes in the study
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period. Statistical analysis. Categorical variables were compared with Chi square test or
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Fisher exact test depending in the number of episodes per comparison group. Continuous
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variables were compared between the two groups according to their distribution(T-student
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or Mann Whitney test).The risk for an uneventfully resolution was evaluated between the
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exposed and non exposed groups calculating the odd ratio (OR) with the respective 95%
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confidence interval (C.I.). Statistical analyses were performed with the Sigma Stat 3.0
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Program and Systat Software, CA, USA.
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Results
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Population characteristics
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Between July 2012 and December 2015, a total of 1121 episodes of FN were evaluated in
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the five Hospitals participating in the study, of which 951 (85%) episodes were enrolled
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and 170/1121 (15%) were excluded, because 97/170 (57%) children and their parent
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refused to participate, 68/170 (40%) episodes did not meet the inclusion criteriaand 5/170
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(3%) had incomplete data. The 951 episodes enrolled were evaluated for bacterial and viral
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infections and all received empiric antimicrobial therapy. Three hundred and nineteen/951
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episodes (34%) had a positive NP sample for respiratory viruses at admission and were
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negative for a bacterial pathogen. Forty eight hours later, 176/319 (55%)of these episodes
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met all criteria for randomization, of which, 92/176 (52%) were randomized into a current
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antimicrobial management and 84/176 (48%) into antimicrobial withholding. At the time
215
of randomization, median ANC was 132/mm3 and 207/mm3in the maintenance and
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withholding antimicrobial group, respectively (P=0.15), with 87% and 80% of children
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having an ANC ≤ 500/mm3 in each group (P=0.3).From 143 episodes positive for a
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respiratory virus and negative for a bacterial pathogen not randomized, 109 did not have a
219
favorable evolution after 48 hours of antimicrobial therapy (104 maintain fever or CRP >
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90 mg/L, 5 had hemodynamic instability), 21 had new clinical foci and 13 were not
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randomized by no adherence to the protocol (Figure 1).
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Table 1 describes the main characteristics of children with episodes of FN and a positive
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respiratory viral infection randomized to both groups. Age, gender, type of cancer and other
224
characteristics were similar between the two groups (P=NS). Less than 10% of children in
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each group received prophylaxis other than trimethoprim-sulfamethoxazole for
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Pneumocystis jiroveci. Eighty eight/176 episodes (50%) had a high risk FN. Of 176
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episodes randomized, 65/92 (71%) and 66/84 (78%) respectively had clinical
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characteristics suggesting an upper/lower respiratory tract infection at the time of
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admission.
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Outcome of children with febrile neutropenic episodes by study groups.
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Table 2 shows the outcome of 176 randomized children, according to intervention. As
232
expected, median days of antimicrobial therapy was significantly different in children that
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maintained (7 days, IQR 7-9 days) compared to children in whom antimicrobials were
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withdrawn (3 days, IQR3-4 days), P<0.0001. Percentage of episodes of FN with uneventful
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resolution was 89/92 (97%) and 80/84 (95%) respectively (P=NS), OR 1.48. (95% C.I.
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0.32-6.83), P=0.61. Days of fever (2 and 1), days of hospitalization (6 and 6) and
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development of a demonstrated/probable invasive bacterial infection (2% and 1%) were
238
similar among groups. No deaths occurred.
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Three children had a demonstrated/probable bacterial infection, two had bacteremia caused
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by ESBL (+) Klebsiella pneumoniae in the group maintaining antimicrobials and one case
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of a culture negative sinusitis in the antimicrobials withholding group. Reinstallment of
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antimicrobial therapy was indicated in 4 children. All 4 had acute myeloid leukemia, were
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admitted with a high risk FN and met study criteria for upper respiratory viral infection. In
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the 4 cases the antimicrobials were discontinued with children in good clinical conditions,
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temperature < 38°C and CRP < 90 mg/L, according to the protocol. Three of them
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presented with fever between days 5 and 7 after admission, without an identifiable new foci
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or clinical deterioration and with CRP < 90 mg/L. The clinical course was favorable in
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three of the children with fever declining after one day of new antimicrobial therapy, in
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absence of any bacterial pathogen detection. The fourth child developed fever on day 5 and
250
an increase in CRP to 100 mg/L. Clinical and imaging findings suggested sinusitis
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requiring a 14 days of antimicrobial therapy. The child did not develop sepsis and was not
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admitted to PICU. He was discharged with a diagnosis of probable invasive bacterial
253
infection.
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One child from the group that maintained antimicrobials developed sepsis and was admitted
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to the PICU. She was a 3 year old girl with a neuroblastoma, a high risk FN and an upper
256
respiratory infection. At the day of randomization, she was afebrile and CRP value was 14
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mg/L. On day 6 she presented with fever and hemodynamic instability. Blood cultures
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obtained at day 6 were positive for an ESBL (+) Klebsiella pneumoniae, CRP value
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increased up to 250 mg/L and she was admitted to PICU receiving antimicrobials based on
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the bacterial isolation by a new period of 14 days, with good clinical outcome. No deaths
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occurred among the 176 randomized children through the study period.
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We performed a separated analysis of the 176 episodes randomized according to the risk
263
status for invasive bacterial infection determined at admission. For the 88 children with
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episodes of low risk FN the median days of antimicrobial therapy was 7 days (IQR 7-9) and
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3 days (IQR 3-3), P<0.001; with 98 and 100% of episodes with uneventful resolution,
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without cases of antimicrobials reinstallment, development of sepsis and admission to
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PICU. In the 88 episodes of high risk FN, the median days of antimicrobial therapy was 7
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days (IQR 7-9) and 4 days (IQR 3-5), P<0.001, with 93% of episodes with uneventful
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resolution in both groups, with the 4 cases of antimicrobials reinstallment and 1 case of
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sepsis and admission to PICU, all of them described previously.
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Respiratory viruses identified in each study group
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The main respiratory viruses identified in the 176 children randomized with episodes of FN
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are described in Table 3. Overall, the most common respiratory virus was rhinovirus (41%)
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followed by RSV, parainfluenza and influenza virus with no differences observed between
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groups. These four viruses represented 88% of the identified respiratory viruses in both
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groups. We detected 23 and 22 cases of viral co-infection in each group. In 43/45 cases
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(96%) viral co-infection included two respiratory viruses. Three of the 4 children requiring
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antimicrobials reinstallment had RSV and one of them a rhinovirus. The child that
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developed a Klebsiella pneumonia sepsis had a positive parainfluenza virus detection.
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Discussion
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Respiratory viruses were detected as sole pathogens in one third of children with cancer
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admitted because of a febrile neutropenic episode of which near half met study criteria of a
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favorable evolution at 48 hours allowing their randomization. Overall, 95% of the episodes
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in which antimicrobials were withdrawn had an uneventful resolution.
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We previously demonstrated that it was possible to apply a selective management,
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proposing ambulatory therapy in children with low risk FN, defined according to the
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following parameters: type of cancer, hemodynamic stability, CRP values, platelet count
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and number of days since the last chemotherapy26. In this study, we advance a step further,
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including the possibility to stopped antimicrobial therapy after 48 hours of admission in
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children with a positive respiratory viral infection, a negative bacterial infection and a
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favorable clinical course, including episodes of low and high risk for invasive bacterial
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infection.
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Knowledge on the epidemiology of respiratory viral infection in immunocompromised
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children is scarce with few systematic studies aimed to determine their clinical impact6.
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RSV, influenza, parainfluenza, adenovirus and picornaviruses have been the most common
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etiologic agents detected in this population 6,7,12. The increasing detection of viruses
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highlights the relevance of optimizing viral diagnosis in children with FN 1.
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Children with cancer and high risk FN require immediate hospitalization and aggressive
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intravenous antimicrobial treatment. We observed an uneventful resolution in 96% of all
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randomized FN episodes, despite the fact that 50% of them were classified as high risk at
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admission. Considering these data, systematic evaluation for respiratory viruses at the time
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of hospital admission could be helpful to establish a more rational treatment in a selected
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group of patients. Miedema and cols.18 recently reported that it is safe to shorten
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antimicrobial treatment to 72 hours in selected medium-risk children withFN;
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antimicrobials were stopped in 50 episodes and no failures were observed, however, no
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high risk episodes were included in this study.
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Approximately 79% of episodes of FN do not present a serious bacterial infection 28,
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therefore a more extensive assessment with multiplex blood and respiratory PCR assays
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could increase pathogens detection6,24, 29, facilitating a tailor-made therapy and reducing
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unnecessary antimicrobial exposure3.
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This study had limitations, including that the intervention was not double blind. We
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decided not to conduct a double blind study because the majority of these children received
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antimicrobial therapy using their CVC. We preferred not to use the CVC in children with
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antimicrobials withholding in order to avoid not necessary manipulations. Another possible
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issue is that not all children randomized in this cohort with respiratory viruses detection
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presented an upper or lower respiratory tract infection at the time of admission. Although
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positive-PCR detection is not always necessarily related with respiratory disease30, the
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majority of children in this study (75%) presented respiratory symptoms, suggesting a role
320
of the respiratory viruses detected by PCR.
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In conclusion, we suggest incorporating molecular respiratory viral study in the initial
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evaluation of all children with cancer and episodes of FN. The reduction of antimicrobial 323
use in children with FN with a demonstrated respiratory viral infection, based on stringent 324
clinical and microbiological/ molecular diagnostic criteria could favor the adoption of 325
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evidence-based and more rational management strategies in this population. 326
Funding
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This work was supported by the National Fund for Scientific and Technological
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Development (FONDECYT), Chile [grants numbers 1120800, 1130911].
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Acknowledgment 332
We thank research nurses of the participant hospitals for their invaluable support in enroll
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patients and obtain blood and nasopharyngeal samples. We appreciate the support provided
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by Magdalena Castro, RN and clinical epidemiologist in the statistical analysis. We thank
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FONDECYT Program for their support
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References 338
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Legends of Tables and Figures
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Figure 1. Episodes of fever and neutropenia evaluated, enrolled and randomized during
417
study period
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Table 1. Admission characteristics of 176 episodes of fever and neutropenia in children
419
with a demonstrated respiratory viral infection, according to intervention
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Table 2. Outcome of 176 children with fever, neutropenia and a demonstrated respiratory
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viral infection, according to intervention
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Table 3. Respiratory viruses identified in 176 children with episodes of fever and
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neutropenia, according to intervention
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Type of Intervention
5 (3-9) 40 (44)
4 (3-8) 46 (55)
0.57 0.13
49 (53) 7 (8) 36 (39) 43 (47) 27 (29) 77 (84) 2 (1-4)
55 (66) 4 (5) 25 (29) 45 (54) 26 (31) 68 (81) 2 (1-3)
0.09 0.43 0.19 0.36 0.81 0.63 0.10
13 (16) 44 (52) 22 (26) 5 (6) 0
0.37 0.37 0.85 0.87
19 (20) 42 (46) 23 (25) 6 (7) 2 (2)
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Antimicrobial withholding N = 84
Age in years, median (IQR) Male gender, n (%) Type of cancer, n (%) Leukemia/Lymphoma Leukemia relapse Solid tumors High risk for invasive bacterial infection, n (%) Use of G-CSF, n (%) Use of CVC, n (%) Hours of fever previous to admission, median (IQR) Admission clinical diagnosis, n (% ) Fever without focus Upper respiratory infection Lower respiratory infection Intestinal focus Others†
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G-CSF: granulocyte-colony stimulating factor; CVC: central venous catheter; IQR: Interquartile range *None of the characteristic differences between groups were significant † Others: Skin/soft tissue infection
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Maintain Antimicrobial N =92
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Type of intervention
Days of antimicrobial therapy, median (IQR) Days of fever after admission, median (IQR) Days of hospitalization, median (IQR) Days of ANC < 500/mm3, median (IQR) Days of AMC < 100/mm3, median (IQR) Resolving uneventfully, n (%) Demonstrated/probable invasive bacterial infection, n (%) Reinstallment of antimicrobials, n (%) Development of sepsis, n (%) Admission to PICU, n (%) Death, n (%)
Total
Maintain Antimicrobial N =92
Antimicrobial Withholding N = 84
7 (7-9) 2 (1-3) 6 (4-8) 5 (3-8) 3 (0-6) 89 (97) 2 (2)
3 (3-4) 1 (1-2) 6 (4-7) 4 (3-8) 2 (0-5) 80 (95) 1 (1) 4 (5) 0 0 0
1 (1) 1 (1) 0
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ANC: absolute neutrophil count; AMC, absolute monocyte count; PICU, pediatric intensive care unit; IQR: Interquartile range
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6 (3-7) 1 (1-2) 6 (4-7) 5 (3-8) 3 (0-5) 169 (96) 3 (2) 4 (2) 1 (1) 1 (1) 0
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< 0.0001 0.44 0.65 0.23 0.46 0.61 0.93
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Type of intervention Maintain Antimicrobial * N=92
Antimicrobial Withholding † N = 84
Total ‡
49 (53) 17 (19) 21 (23) 14 (15) 4 (4) 5 (5) 5 (5) 1 (1)
42 (50) 24 (29) 18 (21) 8 (10) 5 (6) 2 (2) 5 (6) 1 (1)
91 (41) 41 (19) 39 (18) 22 (10) 9 (4) 7 (3) 10 (5) 2 (1)
Rhinovirus Respiratory sincytial virus Parainfluenza Influenza Metapneumovirus Adenovirus Bocavirus Coronavirus
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* 23 episodes with viral co-infection. Twenty one cases with 2 respiratory viruses and 2 cases with 3 respiratory viruses † 22 episodes with viral co-infecction All cases with 2 respiratory viruses ‡ Without significant differences between groups
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Febrile Neutropenia Episodes (n=1121)
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170 episodes excluded: - 97 reject informed consent - 68 not meet inclusion criteria - 5 incomplete data
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Enrolled Episodes (n=951)
No pathogen detected (n=356)
Respiratory Virus (+) Bacteria (-) (n=319)
3
Randomized Episodes (n=176)
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Maintain antimicrobial therapy (n=92)
Respiratory Virus (+) Bacteria (+) (n=122)
143 episodes excluded: - 109 Unfavorable evolution (fever, CRP ≥90mg/L, hemodynamic instability) - 21 New clinical foci - 13 No adherence to protocol criteria
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Respiratory Virus (-) Bacteria (+) (n=154)
Withhold antimicrobial therapy (n=84)