ORIGINAL STUDIES
Frequency and Clinical Outcome of Respiratory Viral Infections
and Mixed Viral-bacterial Infections in Children With Cancer,
Fever and Neutropenia
Juan P. Torres, MD, PhD,* Yenis Labraa, MD,* Carolina Ibaez, MD,* Pilar Kasaneva, MD,*
Mauricio J. Farfn, PhD, Vernica De la Maza, RN,* Milena Villarroel, MD,* Ivonne Vergara, BQ,
Paula Piemonte, MD, Marcela Zubieta, MD, Carmen Salgado, MD, Juan Tordecilla, MD,
Santiago Topelberg, MD, Miguel ORyan, MD,|| and Mara E. Santolaya, MD*
Background: The role of respiratory viral infections (RVIs) as a cause of
overall fever and neutropenia (FN) episodes in children with cancer has
been less characterized than bacterial infections. We conducted a study
aimed to determine the frequency of RVI in children with low compared
with high risk for invasive bacterial infection (IBI) FN episodes and com-
pare the clinical outcome of RVI and mixed RV-bacterial infections.
Methods: Prospective, multicenter study in children with cancer and FN
admitted to pediatric hospitals in Chile between May 2009 and January
2011. Children were evaluated by clinical examination and laboratory tests,
including bacterial cultures and their risk for IBI. Nasopharyngeal sample
was obtained for the detection of 17 respiratory viruses using polymerase
chain reactionDNA microarray platform.
Results: A total of 331 episodes of FN in 193 children were enrolled of
whom 55% were male, with the median age of 7 years and 61% had a hema-
tological malignancy. A viral and/or bacterial pathogen was detected in
67% (224/331) episodes. Overall, RVIs were associated with 57% of FN of
which one-third were mixed RV-bacterial infections. Bacterial infection was
detected in 29% (97/331). Children classified at admission as high risk for
IBI had a similar overall proportion of RVI compared with low-risk group.
Respiratory syncytial virus (31%) and rhinovirus (23%) were the most fre-
quently detected respiratory viruses, followed by parainfluenza (12%) and
influenza A (11%). Children detected with any respiratory virus had fewer
days of hospitalization and a significantly lower probability of hypotension
and admission to pediatric intensive care unit irrespective of their risk clas-
sification status at admission when compared with children with mixed RV-
bacterial or bacterial infections (P < 0.05). All children with a sole RVI had
favorable outcome.
Conclusions: RVIs were the most frequently detected agents irrespective
of their initial risk assessment for IBI. The clinical outcome of mixed RVI
was similar to sole RVI episodes as well as for bacterial infections compared
with mixed viral-bacterial infections. Systematic and early detection of RVI
Accepted for publication April 3, 2012.
From the *Department of Pediatrics, Hospital Luis Calvo Mackenna, Center
for Molecular Studies, Hospital Luis Calvo Mackenna, Faculty of Medi-
cine, Universidad de Chile, Laboratory of Molecular Biology, Clnica Las
Condes, Department of Pediatrics, Hospital Exequiel Gonzlez Corts,
Hospital Roberto del Ro, Faculty of Medicine, Universidad de Chile, and
||Program of Microbiology and Mycology, Faculty of Medicine, Universidad
de Chile, Santiago, Chile.
Supported by FONDECYT government grants 11080113 and 1090194. The
authors have no other funding or conflicts of interest to disclose.
Address for correspondence: Juan P. Torres, MD, PhD, Department of Pediatrics,
Division of Pediatric Infectious Diseases, Hospital Luis Calvo Mackenna,
Antonio Varas 360, Providencia, Faculty of Medicine, Universidad de Chile,
Santiago, Chile. E-mail: jptorres@clc.cl.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journals website (www.pidj.com).
Copyright 2012 by Lippincott Williams & Wilkins
ISSN: 0891-3668/12/3109-0889
DOI: 10.1097/INF.0b013e31825c4b7e
The Pediatric Infectious Disease Journal Volume 31, Number 9, September 2012 www.pidj.com |889
in children with cancer and FN might help to optimize their management by
reducing hospitalization and antimicrobial use.
Key Words: respiratory viral infection, fever, neutropenia, children, cancer
(Pediatr Infect Dis J 2012;31: 889893)
I
nfections are the main cause of morbidity and mortality in chil-
dren with cancer, especially during chemotherapy-induced neu-
tropenic periods.1 During the past decades, research efforts have
been directed at rapidly identifying children at high risk for a severe
bacterial infection to prevent mortality.2 The role of respiratory
viruses (RVs) as a cause of overall and severe fever and neutropenia
(FN) episodes in children is not well characterized.
RVs are believed to be common in children presenting with
FN episodes who are at low risk for invasive bacterial infection
(IBI) and to be uncommon in children with high-risk FN episodes,
but data to support this statement are scarce. In addition, a common
perception in the high-risk group is that respiratory viral infections
(RVIs) tend to be severe and/or prolonged.38
Diagnosis of RVs has relied mainly on viral culture tech-
niques and antigen detection methods limited to a few viruses.6
Using conventional and molecular techniques, respiratory syncy-
tial virus (RSV), rhinovirus, parainfluenza and adenovirus have
been the most frequently detected viruses in patients with cancer
and fever ranging in frequency from 5% to 44%.6,9,10 Arola et al6
reported RVI in 37% of 75 febrile episodes occurring in 32 chil-
dren with cancer using viral culture, antigen detection and serology.
Implementation of gene amplificationbased techniques has signif-
icantly improved our capacity to detect RVs in patients with cancer,
including the detection of new and/or less common viruses such as
bocaviruses, metapneumovirus, coronavirus and others, and occur-
rence of coinfections with >1 RV.911 For example, Koskenvuo et al9
identified RVI in 44% of 138 febrile episodes occurring in children
with leukemia by viral culture, antigen detection and polymerase
chain reaction (PCR). In this series, rhinovirus (22%) followed by
RSV (11%) were most common and 9% of episodes resulted posi-
tive for >1 virus. Murali et al10 studied 82 samples from 70 patients
with hematological malignancies and upper respiratory tract symp-
toms. RV detection increased from 12% by direct fluorescence anti-
body staining to 38% by PCR.
The clinical characteristics and outcome of RV and mixed
RV-bacterial infections in children with an FN episode according
to their IBI risk at the time of admission have not been thoroughly
addressed. If RVI proves to have a relatively benign clinical
course irrespective of the initial IBI risk status of the child, in
opposition to the general perception, management strategies could
be less aggressive in documented RVI. Identifying particular
characteristics of mixed RV-bacterial infections could also
Torres et al The Pediatric Infectious Disease Journal Volume 31, Number 9, September 2012
modulate the management strategy leading to more patient-directed
treatments.
We conducted a large, prospective study combining an
array-based amplification technique for 17 RVs with a protocol-
ized clinical/laboratory assessment for the initial risk classifica-
tion, follow-up and outcome evaluation. Our aim was to determine
the relative frequency of RVs in children with low compared with
high risk for IBI FN episodes and to compare the clinical course
and outcome of RVI and mixed RV-bacterial infections in children
with cancer and febrile neutropenia.
PATIENTS AND METHODS
Overall Study Design
A prospective, multicenter, collaborative, government-
sponsored study was conducted between May 1, 2009, and January
31, 2011, in the 3 main pediatric hospitals in Santiago, Chile (Luis
Calvo Mackenna, Roberto del Ro and Exequiel Gonzlez Corts).
Patients 18 years of age with cancer and FN episode were evalu-
ated at admission by one of the investigators and were invited to par-
ticipate and enrolled if parents or legal guardians signed an informed
consent. Patients with hematopoietic stem cell transplant and/or
solid organ transplant were excluded. The study was approved by
the Ethical Committee and the Directors of each hospital. Children
enrolled were treated in the 3 hospitals according to a common pro-
cedure for evaluation and management of FN episodes, including an
initial risk assessment for IBI by a validated standard.12 The protocol
included a clinical and laboratory evaluation, a virological evalua-
tion and a bacteriological assessment at the time of admission. After
complete resolution of the FN episode, an external evaluator defined
the etiology of each episode as sole RVI, mixed RV-bacterial infec-
tion, sole bacterial infection or an episode of unknown etiology.
Clinical and Laboratory Evaluation
All patients were uniformly evaluated for admission follow-
ing a protocol used in previous studies,12 recording the following
variables: (1) demographics: age, gender, weight, height; (2) can-
cer characteristics: cancer type, type of chemotherapy, start and end
date of last cycle; (3) characteristics of the febrile episode: hours of
fever, type of FN (high or low risk for IBI12), overall clinical status
(evaluated by one of the investigators), axillary temperature, heart
rate, respiratory rate and blood pressure, signs and/or symptoms
indicative of an infectious foci; (4) laboratory tests: white cell count,
absolute neutrophil count (ANC), absolute monocyte count (AMC),
hemoglobin level, platelet count, quantitative C-reactive protein
(CRP) and chest radiograph; (5) Pediatric Risk Mortality score.13
Detection of RVs
A nasopharyngeal sample was obtained in all admitted
patients (Copan nasopharyngeal flocked swabs, Brescia, Italy);
the swab was then inserted into a vial containing viral transport
medium (universal transport medium [UTM-RT] System, Copan)
and stored frozen at 80C for further analysis. Total nucleic acid
was extracted (easyMAG NucliSens; bioMrieux, Inc, Durham,
NC) from samples and qualitative detection of 17 RVs (influenza
A, B and C viruses; parainfluenza 1, 2, 3, 4a and 4b viruses; RSV A
and B; rhinovirus; adenovirus; echovirus; bocavirus; coronavirus;
metapneumovirus A and B) was performed on a platform of PCR
and low-density microarray, according to manufacturers instruc-
tions1416 (PneumoVir, Genomica, Spain).
Bacteriological Assessment
For all episodes, semiautomated blood cultures (central and
peripheral samples in children with central venous catheter; BacT/
890 | www.pidj.com
Alert, bioMrieux, Inc) and a complete urinalysis and urine cul-
ture were obtained at admission; cultures from other locations (skin
lesions, cerebrospinal fluid, bronchoalveolar fluid, stools) were
obtained if clinically indicated.
Patient Treatment and Follow-up
Patients classified as high risk for IBI were treated empiri-
cally with an antipseudomonal (third-generation cephalosporin
plus an aminoglycoside) and antistaphylococcal -lactam antimi-
crobial, and patients classified as low risk were treated empirically
with ceftriaxone after standard treatment protocols.17 Children were
monitored daily throughout their clinical course until fulfilling 2
days with T <38C, 2 consecutive CRP values <40 mg/L, increas-
ing ANC and AMC values and platelets 50,000/mm3. Hemato-
logical, biochemical and microbiological tests were repeated at
defined, previously standardized intervals according to the clinical
evolution.12 Admission to the pediatric intensive care unit (PICU)
during hospitalization and length of stay was registered.
Definitions
Neutropenia: ANC <500/mm3; fever: single axillary
T 38.5C or 38C in 2 measurements separated by 1 hour;
high-risk FN: an FN episode with one of the following risk factors
at the time of admission: (1) relapse of leukemia as cancer type,
(2) hypotension or (3) quantitative CRP 90 mg/L or an FN epi-
sode with the following 2 factors at the time of admission: (4) 7
days between the end of the last chemotherapy and the beginning
of the fever and (5) platelet count12 50,000/mm3; low-risk FN:
an FN episode without the factors described above or the presence
of platelet count <50,000 mm3 or 7 days since last chemother-
apy as a sole risk factor at the time of admission12; RVI: detection
of 1 RV by molecular techniques; bacterial infection: bacteremia
(presence of one or more positive blood cultures, except coagulase-
negative Staphylococcus, for which 2 positive blood cultures were
required) or isolation of a microorganism in a normally sterile site;
mixed RV-bacterial infection: RVI as defined in addition to a bacte-
rial infection as defined.
Statistical Analysis
Differences between 2 groups were tested using the t test
or the Mann-Whitney test, according to data distribution. Differ-
ences between >2 groups were tested using analysis of variance
or Kruskal-Wallis, according to data distribution. The 2 test with
Yates correction for continuity was used for associations between
categorical variables. All tests were 2 tailed, and a P value of <0.05
was considered significant. For all statistical analyses, SigmaStat
software, version 3.0 (SPSS Science, Chicago, IL), was used. Sam-
ple size was calculated based on estimated proportions of estimated
viral infections (45%) and bacterial infections (35%) in children
with FN. A sample size of 330 patients is necessary to estimate
the proportion in our sample to be within 5% for viral infections,
whereas only 305 would be required for bacterial infections using a
95% confidence interval. The sample size for this study will, there-
fore, be 330 to provide adequate precision for both groups.
RESULTS
Description of the Population
A total of 364 episodes of FN were admitted to the
participating hospitals during the 21-month study period of
which 331 episodes (91%), occurring in 193 children, consented
to participate. The median age of children was 7 years (IQ range
412), 55% male and 61% had a hematological malignancy
(leukemia, lymphoma and leukemia relapse). Of the 331 episodes,
2012 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal Volume 31, Number 9, September 2012 Fever and Neutropenia

194 (59%) were classified as high risk for an IBI, presenting at
the time of admission with higher temperature, serum CRP values
and presence of hypotension, and lower ANC and AMC levels,
compared with low-risk episodes. Clinical and laboratory variables
for both risk groups and all study subjects are presented in Table 1.
A viral and/or bacterial pathogen was detected in 67%
(224/331) episodes. An RVI was detected in 57% (190/331) epi-
sodes and a bacterial infection was detected in 29% (97/331). Of
the 190 RVI episodes, 63 (33%) had a mixed RV-bacterial infection.
Frequency of RVs Detected in Children With High-
and Low-Risk FN Episodes
RVs were the most common agents detected, irrespective
of the initial IBI risk classification of children (see Figure, Sup-
plemental Digital Content 1, http://links.lww.com/INF/B216). The
detection of any RVs in the high-risk group was 57% (109/194)
compared with 59% (81/137) in the low-risk group (P > 0.05),
including both sole RVI and mixed RV-bacterial infections. When
only sole RVIs were compared, we detected 32% (61/194) episodes
in the high-risk group compared with 48% (66/137) in the low-risk
group (P = 0.003).
The frequency of mixed RV-bacterial infections and bacte-
rial infections was significantly higher in the high-risk group [25%
versus 11% (P = 0.003) and 13% versus 6% (P = 0.04), respec-
tively].
Frequency of Detection of RVs as Sole RVI, Mixed
RVI and Mixed RV-bacterial Infection
In the 190 RV-positive FN episodes, we detected a total of
241 RVs. The distribution of the detected viruses in FN episodes
classified as sole RVI, mixed RVI and mixed RV-bacterial infection
was as follow: 31% RSV, 23% rhinovirus, 12% parainfluenza, 11%
influenza A, 11% bocavirus, 6% human metapneumovirus, 5% ade-
novirus and 1% coronavirus. RSV, rhinovirus, parainfluenza and
influenza A were detected mostly as a sole RVI, whereas bocavirus
and human metapneumovirus were more frequent as mixed RVI
(Table 2).
No difference in the frequency of the type of RV detected
was observed between high- and low-risk episodes. Similarly,
the frequency of sole RVI in high- and low-risk group was 41%
(80/194) versus 48% (66/137) and the frequency of mixed RVI
between both groups was 15% (29/194) versus 11% (15/1379)
(P > 0.05).
Clinical Presentation and Outcome of RVI,
Bacterial Infections and Mixed RV-bacterial
Infections in Children With Cancer and Febrile
Neutropenia
Clinical Presentation
With the detection of one or more RV in 190 FN episodes,
nasal congestion was reported in 29% compared with 17% of RVI-
negative FN episodes (P = 0.01). Abnormal breath sounds at admis-
sion (wheeze and/or crackles) were more common in RVI-positive
FN episodes (23% versus 10%) (P = 0.003). A nonsignificant trend
toward increased cough and odynophagia was observed in RVI-
positive FN episodes compared with RVI-negative episodes (34%
versus 24% and 11% versus 7%, respectively). Significant differ-
ences were observed between FN episodes caused by RVs com-
pared with bacterial infections in terms of higher CRP and Pediatric
Risk Mortality score at admission (Table 3).

TABLE 1. Overall Characteristics of 331 Fever and Neutropenia Episodes at the Time of Admission According to the
Risk for an Invasive Bacterial Infection

High Risk (n = 194) Low Risk (n = 137) Total (n = 331)

Demographic variables
Age in years (median; p2575%) 10 (513)* 7 (412)* 7 (412)
Male gender (n; %) 101 (52) 82 (60) 183 (55)
Clinical and laboratory variables
Type of cancer (n; %)
Leukemia/lymphoma 84 (43) 70 (51) 154 (47)
Solid tumor 34 (18)* 56 (41)* 90 (27)
Leukemia relapse 46 (23) 0 46 (14)
Others 30 (16) 11 (8) 41 (12)
Hours of fever before admission (median; p2575%) 1 (14)* 2 (14)* 2 (14)
Temperature (C) (median; p2575%) 38.2 (37.938.6)* 38 (37.538.4)* 38.2 (37.838.5)*
Absolute neutrophil count (median; p2575%) 11 (0136)* 115 (0340)* 39 (0206)
Absolute monocyte count (median; p2575%) 0 (032)* 22.5 (0136)* 0 (073)
C-reactive protein (mg/L) (median; p2575%) 75 (31128)* 25 (1146)* 45 (2090)
*P < 0.05.

TABLE 2. Respiratory Viruses Detected in 190 Episodes of Fever and Neutropenia in Children With Cancer

Respiratory Virus Sole Viral Infection Mixed Viral Infection Mixed Viral-bacterial Infection Total, n (%)

Respiratory syncytial virus 37 14 24 75 (31)

Rhinovirus 25 12 19 56 (23)
Parainfluenza 14 6 9 29 (12)
Influenza A 15 5 7 27 (11)
Bocavirus 4 12 10 26 (11)
Human metapneumovirus 4 7 3 14 (6)
Adenovirus 3 3 5 11 (5)
Coronavirus 2 1 0 3 (1)
Total 104 60 77 241 (100)

2012 Lippincott Williams & Wilkins www.pidj.com |891

Torres et al The Pediatric Infectious Disease Journal Volume 31, Number 9, September 2012
TABLE 3. Clinical Presentation and Outcome of Respiratory Viral Infections, Bacterial Infections and Mixed
Respiratory Viral-bacterial Infections in Children With Cancer, Fever and Neutropenia
Respiratory Viral FN
Episodes (n = 127)
At admission
Median age in years (p2575%) 7 (3.511)
CRP (mg/L) (p2575%) 40* (1580)
PRISM score (median) 1*
Clinical outcomes
Days of fever after admission 2* (13)
(p2575%)
Hypotension (n; %) 3* (2%)
PICU admission (n; %) 7* (5%)
Median days of stay (p2575%) 6*(49)
Days of neutropenia after 4 (27)
admission (p2575%)
Median CRP value 48 h after 58* (31124)
admission (p2575%)
* and , significant P value.
PRISM indicates Pediatric Risk Mortality; NS, not significant P value.
Clinical Outcome
Children with RVI-positive episodes presented significantly
less hypotension and PICU at the time of admission, shorter length
of stay and lower CRP values at the third day of hospitalization com-
pared with children with bacterial positive episodes. No significant
differences were observed in clinical presentation and outcome
between episodes of FN caused by bacterial infections and those
caused by mixed RV-bacterial infections (Table 3). Notably, only
7/127 episodes of FN with a positive RV detection required PICU
admission: 1 patient positive for influenza A who died because of
refractory leukemia (the infection was not the attributable cause
of PICU admission or death); the other 6 cases were all sole RVI
episodes [parainfluenza (3), RSV (2) and influenza A (1)] admitted
to the PICU mainly because of pneumonia for assisted ventilation,
and all cases had a favorable outcome. No other cases of mortality
were reported in any group. We did not detect any difference in
clinical and laboratory variables described in Table 3 between 100
sole RVIs and 27 mixed RVIs (data not shown).
DISCUSSION
Our study is one of the largest series to date demonstrating
that RVIs are common in high-risk and low-risk FN episodes in
children with cancer. Overall, RVIs were associated with 57% of
FN of which one-third were mixed RV-bacterial infections. Children
classified at admission as high risk for IBI had a similar overall
proportion of RVI compared with children admitted with a low-
risk classification, although in the former, a significantly higher
proportion of mixed bacterial-viral infections were observed. RSV
and rhinovirus were the most frequently detected RVs, followed
by parainfluenza and influenza A. Despite all the conventional and
molecular microbiologic studies, in one-third of all episodes, it
was not possible to detect any causative agent. Children with FN
episodes and detection of any RV had fewer days of hospitalization
and a significantly lower probability of hypotension and admission
to PICU irrespective of their risk classification status at admission
than children with mixed RV-bacterial or bacterial infections.
Several groups worldwide have reported viral infections
in this population, with a variable proportion ranging from 5% to
44%.6,9,1820 Most studies have focused on RVs,21,22 suggesting that
they tend to be more severe in immunocompromised patients.23,24
In Chile, a previous study21 reported RV detection by direct immu-
nofluorescent assays for influenza A-B, parainfluenza, RSV and
892 | www.pidj.com
Bacterial FN Mixed Viral-bacterial FN
P
Episodes (n = 34) Episodes (n = 63)
10.5 (313) 7 (411.5) NS
58 (26.5128) 76* (28147) <0.05*
4* 1 <0.05*
2 (16.75) 3* (16.25) <0.05*
9* (26%) 18 (28%) <0.05*
9* (26%) 14 (22%) <0.05*
11.5* (7.717) 11 (6.514) <0.05*
7 (313.7) 5 (39) 0.06
123* (71178) 127 (46193) <0.05*
adenovirus in 25% of 44 FN episodes occurring in 25 children with
acute leukemia, using conventional viral diagnosis. Lindblom et al22
studied viral infections as possible etiologic agents in 90 episodes
of FN by conventional virus-diagnostic approach and RT-PCR,
increasing the detection of RVs, cytomegalovirus, Epstein-Barr
virus and erythrovirus from 29% to 60% when using PCR. Mul-
tiplex PCR assays have been developed allowing the simultaneous
detection of RVs,10,25 economizing the diagnostic workup. Results
of these new methods should be interpreted with care although; for
example, human metapneumovirus and bocavirus which have been
reported,3,26,27 in this study, were detected mostly as RV coinfec-
tions.
A main finding is that all children with a positive RV detec-
tion, in the absence of a positive bacterial detection, had a favorable
outcome. Because all children received antimicrobials, we could
not evaluate the clinical course of RVI in the absence of antibiotic
use. A following step may consider the withholding of antimicrobi-
als in sole RVIs under close monitoring. In addition, the mecha-
nisms and magnitude of the immune response in children with can-
cer and FN infected by an RV should be evaluated in future studies.
To our knowledge, this is the first report showing that the clinical
course of mixed RVI was similar to sole RVI episodes and that bac-
terial infections and mixed RV-bacterial infections also had a simi-
lar, albeit more severe clinical outcome. The increasing detection of
RVs highlights the importance of optimizing viral diagnosis as part
of the workup in children with FN.
Our study had several limitations. A positive detection for an
RV in nasopharynx by molecular techniques does not necessarily
indicate respiratory disease. However, children with positive detec-
tions had significantly more nasal congestion and abnormal breath
sounds compared with RV-negative children. Future studies may
consider determining viral load in sequential samples and correlat-
ing findings with clinical signs and symptoms. A nonfebrile control
group in a different study design could provide additional informa-
tion as to the role of these RVs in this population.
To include each FN as independent unit of analysis, we made
a second examination of the data, considering only the first episode
of FN per child, in the 193 enrolled children (193 FN episodes
compared with 331 FN total episodes). No differences were found
when demographic and clinical variables were compared. There
were no differences in the distribution of viral, bacterial and mixed
RV-bacterial infections according to the risk for an IBI or in the
frequency of the RV detected (data not shown).
2012 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal Volume 31, Number 9, September 2012 Fever and Neutropenia
CONCLUSIONS
Our study showed that in children with cancer, fever and
neutropenia RVs are the most frequent detected agents irrespective
of their initial risk assessment for IBI. The clinical course and out-
come of mixed RVI was similar to sole RVI episodes as well as for
bacterial infections compared to mixed viral-bacterial infections.
Implementation of systematic study and early detection of RVI by
molecular diagnostic techniques in children with cancer and FN
might help to optimize their management by reducing hospitaliza-
tion and antimicrobial use.
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