M A J O R A R T I C L E
Human Rhinovirus Species Associated With
Hospitalizations for Acute Respiratory Illness in
Young US Children
Marika K. Iwane,1Mila M. Prill,1Xiaoyan Lu,1E. Kathryn Miller,2Kathryn M. Edwards,2Caroline B. Hall,3
Marie R. Griffin,4Mary A. Staat,5Larry J. Anderson,6John V. Williams,2Geoffrey A. Weinberg,3Asad Ali,2
Peter G. Szilagyi,3Yuwei Zhu,7and Dean D. Erdman1
1National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, and6Department of Pediatrics, Emory
University School of Medicine, Atlanta, Georgia; Departments of2Pediatrics,4Preventive Medicine, and7Biostatistics, Vanderbilt University Medical
Center, Nashville, Tennessee;3Department of Pediatrics, University of Rochester School of Medicine and Dentistry, New York;5Department of
Pediatrics, Cincinnati Children's Hospital Medical Center, Ohio
April 2005 in 3 US counties. Asymptomatic controls were enrolled between December 2003 and March 2004 and
between October 2004 and April 2005 in clinics. Nasal and throat swab samples were tested for HRV and other
viruses (ie, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, and influenza virus) by
reverse-transcription–polymerase chain reaction, and genetic sequencing identified HRV species and types. HRV
species detection was compared between controls and patients hospitalized during months in which controls were
Results.A total of 1867 children with 1947 ARI hospitalizations and 784 controls with 790 clinic visits were
enrolled and tested for HRV. The HRV-A detection rate among participants $24 months old was 8.1% in the
hospitalized group and 2.2% in the control group (P 5 .009), and the HRV-C detection rates among those $6
months old were 8.2% and 3.9%, respectively (P 5 .002); among younger children, the detection rates for both
species were similar between groups. The HRV-B detection rate was #1%. A broad diversity of HRV types was
observed in both groups. Clinical presentations were similar among HRV species. Compared with children infected
with other viruses, children with HRV detected were similar for severe hospital outcomes and more commonly had
histories or diagnoses of asthma or wheezing.
Conclusions.HRV-A and HRV-C were associated with ARI hospitalization and serious illness outcomes.
The contribution of human rhinovirus (HRV) to severe acute respiratory illness (ARI) is unclear.
To assess the association between HRV species detection and ARI hospitalizations.
Children ,5 years old hospitalized for ARI were prospectively enrolled between December 2003 and
Human rhinoviruses (HRVs), which are prime causes of
the common cold, have been more frequently detected
in upper and lower respiratory tract infections with
the use of modern molecular methods. A causal role of
HRV in lower respiratory tract infection is supported by
isolation of HRV from the lower respiratory tract of
infants and older persons [1–4]. Recent studies suggest
differences in illness severity among HRV species [5, 6]
and a more evident association between asthma exac-
erbation and HRV species C (HRV-C), compared with
other HRV species (ie, HRV-A and HRV-B) [6–9].
Although reverse-transcription polymerase chain re-
action (RT-PCR) enables detection of HRV RNA, in-
cluding HRV-C, which has not been grown in standard
tissue culture, HRV RNA has been detected in children
for prolonged periods, even after symptoms have re-
solved [10–13], and is possibly more prolonged for
asthmapatients[14, 15].Thus, detection maynot reflect
a current illness. To assess the contribution of HRV to
severe respiratory illness, several studies compared HRV
Received 18 April 2011; accepted 9 August 2011; electronically published 19
Presented in part: XI International Symposium on Respiratory Viral Infections,
Bangkok, Thailand, 19–22 February 2009.
Correspondence: Marika K. Iwane, PhD, MPH, National Center for Immunization
and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton
Rd, MS A34, Atlanta, GA 30333 (email@example.com).
The Journal of Infectious Diseases
Published by Oxford University Press on behalf of the Infectious Diseases Society of
0022-1899 (print)/1537-6613 (online)/2011/20411-0009$14.00
d JID 2011:204 (1 December)
d Iwane et al
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detection among hospitalized patients [5, 12, 16, 17] or out-
patients with lower respiratory tract illness [6, 18–20] to HRV
detection among controls without respiratory symptoms; most
but not all studies noted higher HRV detection among partic-
ipants with illness. The study populations, severity of cases, age,
comorbidities, and choice of controls varied by study, with HRV
detection rates for controls ranging widely, from 3% to 32%.
Only 1 US study, involving Alaskan children, compared HRV
detection between hospitalized cases and asymptomatic controls
and did not find significant differences .
Our study aimed to delineate the association of HRV-A,
HRV-B, and HRV-C with serious illness and to compare de-
tection rates between hospitalized children with severe acute
respiratory illness (ARI) and asymptomatic control children
,5 years old in 3 large geographic areas of the United States.
The goal of this study was to determine whether HRV was asso-
ciated with hospitalizations for ARI or fever (collectively referred
age who resided in 3 geographic areas in the United States. The
primary objective was to compare the HRV species detection
rates between 2 groups: hospitalized ARI cases and asymp-
tomatic controls. The secondary objective was to compare the
clinical severity of hospitalized ARI cases with only HRV to
those only with viruses (ie, respiratory syncytial virus [RSV],
pneumovirus [HMPV], and influenza A and B viruses [in-
fluenza]) known to be associated with serious illness
The design and methods of the New Vaccine Surveillance
Network for ARI hospitalizations have been described elsewhere
[21, 22]. The study was approved by the institutional review
boards of each site and the Centers for Disease Control and
Prevention (CDC). Informed consent was obtained from each
parent or guardian prior to enrollment.
Study staff prospectively enrolled children ,5 years of age ad-
mitted to study hospitals in 3 counties (encompassing Rochester,
NY; Nashville, TN; and Cincinnati, OH) from October 2003 to
April 2005 who had an ARI admission diagnosis. Hospital
surveillance was conducted 4 days/week, except during the
2004–2005 influenza season, when it was conducted 7 days/
week. Surveillance was population based, with study hospi-
tals accounting for .95% of the pediatric hospitalizations in
each county. Children were excluded if they had been pre-
viously hospitalized during the prior 4 days, were newborns
hospitalized since birth, had neutropenia from chemotherapy,
or had been ill for .14 days before hospitalization.
1-3 [PIV],human meta-
Children ,5 years of age who resided in one of the 3 study
counties were systematically enrolled as controls at well-child
visits in 8–10 primary care practices if they did not have current
ARI symptoms determined by questioning the family. En-
rollment was conducted 1–2 days/week during December
2003–April 2004 and October 2004–April 2005, as described
elsewhere . Enrolled control children were excluded from
analysis if they subsequently had ARI signs noted in the medical
record for that visit.
Specimen and Data Collection
After obtaining informed consent, study staff collected a nasal
swab specimen (both nares were sampled to the level of nasal
turbinates) and throat (ie, tonsillopharyngeal) swab specimen
and combined them in transport media. Study staff also con-
ducted interviews with parents or guardians and performed
medical record reviews to obtain demographic and clinical data.
A preexisting high-risk medical condition was considered
present if noted in the medical record or if the parent or
guardian responded that a healthcare professional told them
the child had the condition. High-risk medical conditions
corresponded to those included in the Advisory Committee
on Immunization Practices recommendations for influenza
vaccine, including history of cancer; diabetes mellitus; sickle
cell disease; immunodeficiency; disease of the heart, kidney, or
lung (including asthma); and neurologic/neuromuscular con-
ditions, such as seizures, cerebral palsy, or muscular dystrophy
. History of asthma or wheezing included a diagnosis of
asthma, reactive airway disease, or recurrent or chronic
wheezing. We defined 3 clinical variables related to wheez-
ing: (1) acute wheezing, which includes an admission or dis-
charge diagnosis of asthma, bronchiolitis, or wheezing,
consistent with our previous study ; (2) a discharge diagnosis
of asthma (defined as International Classification of Diseases,
Ninth Revision, code 493.xx); and (3) a first-listed discharge
diagnosis of asthma (the likely reason for hospitalization).
Aliquots of combined nasal and throat swab specimens were
stored at 270?C and tested at the CDC for HRV by RT-PCR,
using primers and probes that targeted the highly conserved
HRV 5# noncoding region (5#NCR) that can detect all
100 prototype HRVs and the novel species C strains . To
determine HRV species (HRV-A, HRV-B, and HRV-C) and
type, RT-PCR was performed on all HRV-positive specimens,
using other primers to amplify and sequence a partial region of
the VP1 gene (method available on request). Specimens that
were VP1 negative were further tested using primers that am-
plified partial VP4/VP2 or 5#NCR regions , resulting in
identification of 74% of strains by partial VP1 sequencing, 18%
by VP4/2, and 3% by 5#NCR. Specimens were also tested by
RT-PCR for RSV, PIV, HMPV, and influenza A and B viruses.
Rhinovirus in Hospitalized Children
d JID 2011:204 (1 December)
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by the National Vaccine Program Office (cooperative agreements U38/
CCU217969, U01/IP000017, U38/CCU417958,
CCU522352, and U01/IP000147).
Potential conflicts of interest. K. M. E. received grant funding from
NovartisandpreviouslywasaconsultanttoNexBio.M. R.G. receivedgrant
funding from MedImmune. G. A. W. was on speaker’s bureaus of Merck,
GlaxoSmithKline and Sanofi-Pasteur. C. B. H. has been on a MedImmune
Advisory Board and is a consultant for MedImmune. J. V. W. has served as
a consultant for MedImmune and Quidel. M. A. S. had funding from
MedImmune for RSV studies, was on the MedImmune Advisory Board,
and had funding from Merck and GlaxoSmithKline for rotavirus pre-
sentations and from GlaxoSmithKline for infectious disease studies. L. J. A.
has been a consultant for Novartis, MedImmune, and LigoCyte Pharma-
ceuticals, Inc. A. A. received a 2008 Pediatric Infectious Diseases Society–
MedImmune fellowship. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
The work was supported by the CDC and in part
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