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DOI: 10.1542/peds.2013-2216; originally published online January
13, 2014; 2014;133;e312Pediatrics
Oliveira, Aline Lavado Tolardo and Jonny YokosawaMorun
Bernardino Neto, Nayhanne Tizzo de Paula, Thelma Ftima Mattos
Silva
Loureno Faria Costa, Divina Aparecida Oliveira Queirz, Hlio
Lopes da Silveira,Human Rhinovirus and Disease Severity in
Children
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of Pediatrics. All rights reserved. Print ISSN: 0031-4005.
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60007. Copyright 2014 by the American Academy published, and
trademarked by the American Academy of Pediatrics, 141 Northwest
Pointpublication, it has been published continuously since 1948.
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Human Rhinovirus and Disease Severity in Children
WHATS KNOWN ON THIS SUBJECT: Human rhinovirus has beenknown as
the common cold agent. Recently, studies have reportedthat this
virus is responsible for severe infections of the lowerrespiratory
tract in children. Reports of factors that increasedisease severity
have been contradictory.
WHAT THIS STUDY ADDS: This study identies some of the
factorsinvolved in disease severity in HRV infections in children.
Weexpect that children at risk for developing severe disease
couldbe identied sooner and appropriate measures could be
taken.
abstractOBJECTIVE: To evaluate retrospectively human rhinovirus
(HRV) infec-tions in children up to 5 years old and factors
involved in disease se-verity.
METHODS: Nasopharyngeal aspirates from 434 children presentinga
broad range of respiratory infection symptoms and severity
degreeswere tested for presence of HRV and 8 other respiratory
viruses. Pres-ence of host risk factors was also assessed.
RESULTS: HRV was detected in 181 (41.7%) samples, in 107 of them
asthe only agent and in 74 as coinfections, mostly with respiratory
syncytialvirus (RSV; 43.2%). Moderate to severe symptoms were
observed in28.9% (31/107) single infections and in 51.3% (38/74)
coinfections(P = .004). Multivariate analyses showed association of
coinfectionswith lower respiratory tract symptoms and some
parameters ofdisease severity, such as hospitalization. In
coinfections, RSV was themost important virus associated with
severe disease. Prematurity, car-diomyopathies, and noninfectious
respiratory diseases were comorbid-ities that also were associated
with disease severity (P = .007).
CONCLUSIONS: Our study showed that HRV was a common pathogen
ofrespiratory disease in children and was also involved in severe
cases,causing symptoms of the lower respiratory tract. Severe
disease in HRVinfections were caused mainly by presence of RSV in
coinfections, pre-maturity, congenital heart disease, and
noninfectious respiratory dis-ease. Pediatrics
2014;133:e312e321
AUTHORS: Loureno Faria Costa, PhD,a Divina AparecidaOliveira
Queirz, PhD,a Hlio Lopes da Silveira, MD,a,b
Morun Bernardino Neto, PhD,c Nayhanne Tizzo de Paula,MSc,a
Thelma Ftima Mattos Silva Oliveira, PhD,a AlineLavado Tolardo,a and
Jonny Yokosawa, PhDa
aLaboratory of Virology, Instituto de Cincias
Biomdicas,bHospital de Clnicas, and cInstituto de Gentica e
Bioqumica,Universidade Federal de Uberlndia, Uberlndia, MG,
Brazil
KEY WORDShuman rhinovirus, respiratory disease severity,
children,coinfections, comorbidities
ABBREVIATIONSAdVadenovirusARIacute respiratory
infectionHC-UFUHospital de Clnicas of Universidade Federal
deUberlndiahMPVhuman metapneumovirusHRVhuman
rhinovirusICD-10International Classication of Diseases, 10th
RevisionLRTIlower respiratory tract infectionPIVparainuenza
virusRSVrespiratory syncytial virusURTIupper respiratory tract
infection
Dr Costa conceptualized and designed the study, carried out
theexperiments, analyzed the results, and drafted the manuscript;Dr
Queirz was responsible for sample collection and helpeddesign the
study; Dr Lopes da Silveira carried out the analysis ofall clinical
cases in regard to comorbidities and clinical status,helped devise
the clinical criteria for severity of infections, andrevised the
manuscript; Dr Bernardino Neto performed thestatistical analyses
and revised the manuscript; Ms NayhanneTizzo de Paula helped carry
out the experiments, took part in thediscussion, and revised the
manuscript; Dr Oliveira and MsTolardo helped carry out the
experiments and revised themanuscript; Dr Yokosawa helped design
the study, oversaw theexperimental work and analyses of the
results, and revised themanuscript; and all authors approved the
nal manuscript assubmitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2013-2216
doi:10.1542/peds.2013-2216
Accepted for publication Nov 22, 2013
Address correspondence to Jonny Yokosawa, PhD, Instituto
deCincias Biomdicas, Universidade Federal de Uberlndia,Avenida Par,
1720, Bloco 4C, Uberlndia, MG, 38400-902, Brazil.E-mail:
[email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright 2014 by the American Academy of Pediatrics
(Continued on last page)
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Human rhinovirus (HRV) is one of themost important causes of
respiratoryinfections and has been associatedmostly with the common
cold.1 In chil-dren, this virus is highly common and isresponsible
for lower respiratory tractinfections (LRTIs) with severe
symp-toms.25 Indeed, HRV infections are one ofthemain causes of
bronchiolitis in youngchildren and an inducer of
wheezingepisodes.69
Factors involved in increased diseaseseverity in HRV infections
are contra-dicting in the literature. Some reportshave associated
coinfection with a
sec-ondrespiratoryviruswithamoreseveredisease,10,11 whereas others
have not.7,9
On the other hand, another study hasraised the possibility of a
protective roleof HRV against other viral infections.12
Underlying risk conditions may also beinvolved in disease
severity.9,13 Again,the reports are contradicting; atopicfamily
history has been associated withsevere HRV infection, whereas
exposureto smoking has not,11 and the oppositehas been reported in
another study.9
Furthermore, congenital heart diseasewas considered a risk
factor in 1 study3
but not in another.9 Recently, our groupevaluated the role of
HRV coinfections inchildren with LRTI and observed nosignicant
difference in frequencies ofsevere infections caused by HRV in
sin-gle or coinfections.14 However, the in-vestigation was carried
out only withLRTI cases. To further evaluate the fac-tors that
might be involved in severeillness caused by HRV in young
children,we investigated all HRV cases and in-cluded in the
analyses young childrenpresenting with a wide spectrum of
re-spiratory disease symptoms.
METHODS
Patients and Attendance Settings
This was a retrospective study inwhich eligible patients were
childrenup to 5 years old presentingwith acuterespiratory infection
(ARI) who were
attended by a physician within 5 daysfrom the onset of clinical
symptoms,fromJanuary2001toJune2010.Patientspresented with a broad
spectrum ofrespiratory disease symptoms, and
434inpatientsandoutpatientswereenrolledin the study.
Patients were attended at Hospital deClnicas of Universidade
Federal deUberlndia (HC-UFU) and public healthcenters from 3
different districts of thecity of Uberlndia, Minas Gerais
State,Brazil. Medical and demographic datawere collected through
questionnaireslled out by the physician and includedage, day of
onset of symptoms beforeattendance, clinical presentation,
comor-bidities, household smoking, and atopicdiseases.
This study was approved by the Ethicsand Research Committee of
UFU underprotocol 877/11, and a signed informedconsent was obtained
from each childsparent or foster parent before
samplecollection.
Clinical Criteria
Characteristic ARI symptoms and signswere assigned by the
physician andincluded runny nose, coughing, wheez-ing, and difculty
breathing, with orwithout fever. The clinical diagnosis wasin
accordance with the InternationalClassication of Diseases, 10th
Revision(ICD-10; World Health Organization, 1994).Symptoms of upper
respiratory tractinfection (URTI) included croup,
tracheo-bronchitis, no sibilant bronchitis, commoncold, u, otitis
media, rhinopharyngitis,laryngotracheitis, and laryngitis;
LRTIsymptoms included pneumonia, bron-chopneumonia, bronchiolitis,
sibilantbronchitis, and bronchospasm. If apatient had mixed
symptoms of URTIand LRTI, we considered the latter.
Mild diseases consisted of URTI or wereconsidered so by the
attending physi-cian, following ICD-10, or occurred inpatient who
did not need hospitalizationfor the respiratory illness. Moderate
to
severe symptoms encompassed mostLRTI cases, and were those
consideredby the attending physician as moderateor severe,
following ICD-10, or hospital-ization exclusively due to the
respiratoryinfection. All children with pneumoniaand those who
needed supplementaloxygen or mechanical ventilation weregrouped in
this category.
Bronchiolitis was classied as mild,moderate, or severe according
to theClinical Score of Respiratory Failure inBronchiolitis.15
Clinical scores describedby Taussig et al16 were used to
classifyother LRTI cases.
Underlying Risk Conditions
We identied comorbidities retrospec-tively by consulting the
clinical medicalrecords from HC-UFU or through
theclinicalquestionnairesadministeredbythe attending physician at
the momentof sample collection.
Nasopharyngealaspirateswerecollectedas described17 and tested by
immuno-uorescence assay for detection of re-spiratory syncytial
virus (RSV), inuenzaviruses A and B, parainuenza viruses(PIVs) 1,
2, and 3, and adenovirus (AdV)with the Respiratory Panel I Viral
Screen-ing and Identication Kit (Merck Millipore,Billerica, MA).
Additionally, reverse tran-scription polymerase chain reaction
wasused to detect RSV and inuenza virus,18
PIV 13,19 and human metapneumovirus(hMPV),20 and polymerase
chain reac-tion was used for AdV.21 RT-PCR for HRVwas performed by
using a combinationof 2 protocols.22,23
Detection of pathogens other thanviruses was not carried
out.
Statistical Analysis
Analyseswere performedbyusingx2 tocompare the frequency of
groups ofinfections according to severity ofsymptoms. x2 and P
values were ad-justed through Yates correction usingBioEstat
software version 5.0.24 The
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median age differences were calcu-lated by using nonparametric
MannWhitney t test. For multiple correlationanalyses, canonical
correlation wasused to evaluate the impact of coin-fections on
disease severity and toidentify which coinfection caused moresevere
symptoms. For all tests, calcu-lations were also performed by
usingBioEstat, and P , .05 was consideredstatistically
signicant.
RESULTS
Nasopharyngeal aspirates were col-lected from 434 children 0 to
5 years old(median age = 7.0 months) who pre-sented with ARI, and
at least 1 re-spiratory virus was detected in 383(88.2%) samples
(Table 1), with morecases of children,6 months of age andmale
patients. More severe respiratorydisease predominated in younger
chil-dren, as observed by the higher fre-quencies in this age group
of LRTI, ofhospitalizations, and of moderate- tohigh-complexity
clinical attendances atpediatric ward, ICU, nursery ward, andday
care ward.
HRV and RSV were the most commonagents detected, in 41.7% and
35.9% ofsamples, respectively (Fig 1). AmongHRV-positive cases,
this virus was theonly agent detected in 59.1% (107/181)samples,
and a second virus wasdetected in 40.9% (74/181)
samples,predominantly RSV. The median age ofchildren with HRV
single infections washigher than that of RSV single infections
(9 months and 2 months, respectively;P, .001).
The majority of HRV single infectionsresulted in mild symptoms
(71.0%;Fig 2A). However, in coinfection cases,the frequency of
moderate to severesymptoms was higher (51.4%) thanthat of single
infections (29.0%). Thishigher frequency was probably causedby
presence of RSV, because exclusionof the RSV cases from the
coinfectiongroup led the frequencies of mild andmoderate to severe
cases in this groupto become similar to those of HRVsingle
infections. Furthermore, fre-quencies of cases according to
severityof symptoms were also comparablebetween HRV+RSV
coinfections andRSV single infections.
Despite thepredominanceof symptomsinvolving the upper
respiratory tract(63.6%), more than one-third of the HRVsingle
infections included symptoms ofLRTIs, with many cases of
bronchiolitisand sibilant bronchitis or broncho-spasm (Fig 2B). The
frequencies ofURTIs and LRTIs (Fig 2B) were similar tothose of mild
and moderate to severecases (Fig 2A), respectively, indicatingan
association between the anatomicstructure affected and the severity
ofthe infection. For other groups (HRVcoinfections, HRV
coinfections exclud-ing RSV, HRV+RSV coinfections, and RSVsingle
infections), the frequencies ob-served for moderate to severe
symp-toms were also similar to thoseaffecting the lower respiratory
tract.
Because these results showed in-volvement of RSV with disease
severityin coinfections, amultivariable analysiswas performed to
evaluate the asso-ciation of factors in severe illness(Table 2).
For groups of HRV singleinfections and coinfections excludingRSV, a
direct association was observedbetween these groups and most
URTIs,as indicated by the variables with samesign. In addition, the
association of thecommon cold, bronchitis, and trache-obronchitis
was stronger for the groupof HRV single infection, as indicated
bythe high values (strengths). For theHRV+RSV and RSV single
infectiongroups, the opposite signs indicatedthat no association
exists with mostURTIs. On the other hand, a direct as-sociation was
observed between mostLRTIs, especially bronchiolitis andpneumonia,
and RSV infections, in bothsingle infections and coinfections
withHRV. In clinical parameters of diseaseseverity, the main
associations werebetween RSV infection groups andhospitalization or
moderate to severeclinical symptoms. Early age (,6months) was
associated mainly withRSV infections, whereas HRV single in-fection
and HRV coinfections excludingRSV groups were associated
withinfections in older children.
Furthermore, in HRV coinfection cases,a strong and signicant
associationwas found with LRTI symptoms, clinicalparameters of
disease severity, andpatient age (Table 3). In this
analysis,HRV+RSV coinfection was the most
TABLE 1 Demographic Data on Children ,5 Years Old With ARIs
Age Group, mo N (%) Viral Infection Cases
No. of Cases Male/Female LRTI (%)a URTI (%)a
PatientsHospitalized (%)a
Moderate- to High-ComplexityClinical Attendance (%)a
06 195 (44.9) 175 99/76 119 (68.0) 56 (32.0) 129 (73.7) 140
(80.0)612 68 (15.7) 61 37/24 35 (57.4) 26 (42.6) 15 (24.6) 21
(34.4)1224 92 (21.2) 80 45/35 22 (27.5) 58 (72.5) 15 (18.7) 15
(18.7)$24 79 (18.2) 67 36/31 17 (25.4) 50 (74.6) 10 (14.9) 12
(17.9)Total 434 (100.0) 383 217/166 193 (50.4) 190 (49.6) 169
(44.1) 188 (49.1)a Percentages relative to viral infection cases in
each age group.
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important variable in the correlationanalysis, showing stronger
associa-tions with bronchiolitis, hospitaliza-tion, and early age.
This analysisshowed that RSV was the main con-tributor in the
association with diseaseseverity and LRTIs, conrming theresults
shown in Fig 2. Coinfectionswith PIV also showed some involvementin
disease severity, but with a lowerstrength compared with
HRV+RSVcoinfection.
Underlying risk conditions that couldbeassociated with increased
disease se-verity were also evaluated (Fig 3). InHRV single
infections, the frequency ofmoderate to severe cases was higherin
children who had such conditionsthan in those who did not have
them(24.3% and 4.7%, respectively). Incoinfections, the frequency
of moder-ate to severe cases in the presence ofthese risk factors
was even higher(43.2%). However, when RSV caseswere excluded from
the coinfections,the frequency of moderate to severe
cases in children who had comorbid-ities decreased to a rate
(28.6%) com-parable to those in HRV singleinfections. Furthermore,
frequencies ofmoderate to severe cases in HRV+RSVcoinfections and
RSV single infectionswere similar (59.4% and 58.9%, re-spectively).
These results indicatedthat comorbidities and RSV in coin-fections
may be important factors as-sociated with increases in
diseaseseverity of HRV infections.
Because early age is a known factor indisease severity of RSV
infections, it wasevaluated as a factor in HRV singleinfections
aswell (Fig 4A). The frequencyof moderate to severe cases was
higherin younger children and decreased withage. However, 12 of 19
moderate to se-vere cases of the group of children up to6 months of
age presented with anotherrisk factor, mostly congenital
heartdisease or prematurity. Thus, when wecarried out the analysis
with early ageas the only factor, there was no signi-cant
association with severe symptoms
in comparison with children who didnot have any risk conditions
(Fig 4B). Onthe other hand, prematurity, congenitalheart diseases,
and noninfectious re-spiratory diseases were important un-derlying
conditions associated withmoderate to severe infections. Still,
themedian age of patients in each of thesegroupswas lower
inmoderate to severecases than in mild cases, althoughslight
signicance was observed only inthe prematurity and congenital
heartdisease groups.
DISCUSSION
Viruses may have constituted the majorgroup of pathogens
involved in ARI inchildren up to 5 years old in this study,because
at least 1 virus was detected in88.2% samples. Other studies
alsoreported a high percentage of viral in-fection cases, even
though a highernumber of viruses were tested in thosestudies than
in ours.7,25,26 Still, the highfrequency of viral infections we
detected
FIGURE 1Distribution of cases according to the respiratory
viruses detected by immunouorescence assay or reverse transcription
polymerase chain reaction innasopharyngeal aspirates collected from
0- to 5-year-old children presenting with ARI. Numbers shown above
bars represent the corresponding numbers ofcases. * One case of
inuenza virus B and 1 case each of RSV+AdV, RSV+PIV, AdV+PIV, and
AdV+inuenza virus A.
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could reect the testing for the mainviruses responsible for ARI
in childrenand the application of 2 detectionmethods.
Although some studies reported RSV asthe predominant virus
detected in ARIfollowed by HRV, with detection of thelatter ranging
from 7.2% to 30.0% insingle or coinfection cases,7,9,25 in ourstudy
HRV was predominant, although
it was followed closely by RSV. In thosereports, the studies
were carried outonly with children who were hospital-ized and had
bronchiolitis. In our study,on the other hand, samples were
col-lected from children presenting withrespiratory disease
symptoms rangingfrom mild to severe, and in all seasons.This
difference may account for thehigh percentage of HRV cases we
de-
tected, because this virus was detectedduring all seasons27 and
caused infec-tions with a broad clinical presen-tation. Still, the
number of mild HRVcases could be higher because parentsof children
with mild symptoms areless likely to seek medical care.
In this study, a second respiratory viruswas detected in many of
the patientswith HRV infections. The HRV+RSV
FIGURE 2Distribution of cases according to (A) etiology and
severity and (B) clinical symptoms in childrenup to 5 years oldwith
respiratory infection. Thenumbers aboveand inside bars represent
the corresponding numbers of cases. * Laryngitis and
rhinopharyngitis.
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coinfection predominance could re-ect the high frequency of
these 2infections in children with ARIs, whichwas also reported by
others,7,9,11,13,25
and the overlap in time periods whenoccurrence of respiratory
infectionscaused by both viruses was high, fromFebruary to
June.27
We had shown previously that coin-fection with HRV and another
re-spiratory virus was not associated withdisease severity.14
However, that studywas limited to LRTI cases. To obtaina better
evaluation of factors thatmight be involved in increased
diseaseseverity, in this study we includedpatients who attended
different set-tings in public health service units andpresented
with varying degrees of se-verity of symptoms, with or without
theneed for hospitalization. By doing this,we attempted to decrease
bias causedby factors that may have affected theresults reported
previously, includingours.7,9,14,25
Byperformingmultivariateanalysis,wefoundthatcoinfectionswereassociatedwith
greater disease severity in com-parison with HRV single
infections.However, this association resultedmainly from the
presence of RSV in thecoinfections, because removal of RSVcases
from the coinfection grouprevealed that the severity and fre-quency
of clinical symptoms weresimilar to those inHRVsingle
infections.Investigating the rst episode of bron-chiolitis in
hospitalized infants up to 1year old, Marguet et al7 also
observedmore severe disease in infectionscaused by RSV and HRV+RSV.
However,comparative analysis with coinfectionscaused by HRV and
other viruses wasnot shown in that study.
Although the majority of the HRV singleinfections caused mild
URTI symptoms,approximately one-third of these casesinvolved LRTIs,
which was consistentwiththendingsreportedbyothers7,9,13,25
and was reected directly in the num-ber of severe cases.
In moderate to severe cases, at least 1underlying risk condition
was presentin 83.9% (26/31) of HRV single infec-tions, a nding
similar to those re-ported by others,9,11 whereas in mildcases the
presence of comorbiditieswas observed in only 43.4% (33/76).
TABLE 2 First Canonical Correlation Analysis Between Types of
Infections and Symptoms of URTIs,LRTIs, Clinical Parameters of
Disease Severity, and Patient Age
Groups of Variables Groups According to Virus Found
URTIs (r = 0.366; P , .001)Common cold: (2) 0.484 HRV single
infection: (2) 0.857Bronchitis: (2) 0.458 HRV coinfections
excluding RSV: (2) 0.203Tracheobronchitis: (2) 0.481 HRV+RSV: (+)
0.507Acute otitis media: (2) 0.178 RSV single infections: (+)
0.659Croup: (+) 0.141Laryngotracheitis: (2) 0.161
LRTIs (r = 0.382; P , .001)Bronchiolitis: (+) 0.785 HRV single
infections: (2) 0.787Pneumonia: (+) 0.356 HRV coinfections
excluding RSV: (2) 0.353Sibilant bronchitis: (2) 0.014 HRV+RSV: (+)
0.410Bronchospasm: (+) 0.094 RSV single infections: (+) 0.756
Clinical parameters of disease severity (r = 0.346; P =
.003)Orotracheal intubation: (2) 0.009 HRV single infection: (2)
0.923Mechanical ventilation: (2) 0.164 HRV coinfections excluding
RSV: (2) 0.095Supplementary O2: (2) 0.049 HRV+RSV: (+)
0.347Hospitalization: (+) 0.685 RSV single infections: (+)
0.747Hospitalization .7 d: (+) 0.480Moderate to severe symptoms:
(+) 0.930
Patient age, mo (r = 0.380; P , .001)06: (2) 0.925 HRV single
infections: (+) 0.466612: (+) 0.109 HRV coinfections excluding RSV:
(+) 0.7091224: (+) 0.768 HRV+RSV: (2) 0.315
RSV single infections: (2) 0.753
TABLE 3 First Canonical Correlation Analysis Between HRV
Coinfections and Symptoms of LRTIs,Parameters of Disease Severity,
Comorbidities, and Patient Age
Groups of Variables Coinfecting Virus
LRTIs (r = 0.388; P = .03)Bronchiolitis: (+) 0.813 RSV: (+)
0.923Pneumonia: (+) 0.134 Inuenza virus A: (2) 0.032Sibilant
bronchitis: (+) 0.292 PIV: (+) 0.235Bronchospasm: (2) 0.155 AdV:
(2) 0.224
hMPV: (2) 0.093
Clinical parameters of disease severity (r = 0.539; P ,
.001)Orotracheal intubation: (+) 0.235 RSV: (+) 0.377Mechanical
ventilation: (+) 0.564 Inuenza virus A: (2) 0.147Supplementary O2:
(+) 0.167 PIV: (+) 0.052Hospitalization: (+) 0.956 AdV: (2)
0.194Moderate to severe symptoms: (+) 0.649 hMPV: (2) 0.101
No underlying diseases: (2) 0.901
Patient age, mo (r = 0.397; P = .03)06: (2) 0.790 RSV: (2)
0.657612: (2) 0.153 Inuenza virus A: (+) 0.3811224: (+) 0.889 PIV:
(+) 0.099$24: (+) 0.144 AdV: (+) 0.713
hMPV: (+) 0.106
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Brand et al9 suggested that comorbid-ities, not coinfections,
might be impor-tant factors associated with severity
inchildren.
Prematurity alters normal lung de-velopment and results in
chronic lungdiseases.28 Thus, the premature childmay be at higher
risk of developinga more severe respiratory disease re-gardless of
whether the virus causingthe infection is HRV or RSV.29 This
pos-sibility was supported by our study,because we also observed an
associa-tion between prematurity and diseaseseverity in HRV single
infection. Similarto our ndings, Watanabe et al3 showedinvolvement
of congenital heart dis-eases in severe HRV infection. In
addi-tion, we also observed the involvementof noninfectious
respiratory diseaseswith more severe disease.
Our data also showed that the numberof viral infections was
highest in chil-dren ,6 months old who had a moresevere prognosis,
which was indicatedby higher frequencies of hospital-izations,
LRTIs, and cases that neces-sitated moderate- to
high-complexityclinical interventions. Children in thisage group
may be at higher risk ofhaving more severe disease, probablybecause
of their immature immunesystems.
In HRV single infections, moderate tosevere cases occurred
mainly in pa-tients up to 1 year old, suggesting thatyoung children
may be more suscepti-ble to severe respiratory infectionscaused by
HRV, as also proposed byothers.25,30 Bronchiolitis, sibilant
bron-chitis, and bronchospasm cases wereobserved in nearly 30% of
all HRV single
infections, indicating that HRV might be1 of the main causes of
wheezing ininfants.31 However, in our analyses earlyage as the only
factor presented by thechild did not show an association
withmoderate to severe infection. Instead,a combination with
underlying condi-tions might be needed to cause moresevere
disease.
Many of the cases we evaluated were ofchildren presenting with
moderate tosevere symptoms, and we observeda signicant difference
in frequency ofmore severe cases in those who pre-sented with
comorbidities (Fig 3).However, children with mild re-spiratory
disease usually do not needmedical care, and in 1 study,32
physi-cian consultations, as an indicator ofdisease severity, were
associated with25.4% of respiratory illnesses in the
FIGURE 3Distribution of cases according to severity of symptoms
and presence or absence of underlying risk conditions. The values
above bars represent thecorresponding number of cases. P values
were calculated by comparing the number of patients who did not
present (A) with those who presented (P) withunderlying risk
conditions, according to the severity of symptoms in each
group.
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community, with 17.6% of the HRVcases resulting in medical
attention.The impact of risk factors in HRVinfections in the
community remains tobe evaluated.
Although this study assessed the in-volvement of some factors in
severity ofHRV infections, we did not investigate therole of
bacteria, such as Streptococcusand Haemophilus, in these cases. It
isalso possible that viruses that were nottested or are still
unknown could havecaused more severe disease. On theother hand,
detection of a pathogen, es-pecially with the use of polymerase
chainreaction, does not indicate that thispathogen is the causative
agent of thedisease. Studies have shown that re-spiratory viruses
can be detected in upto 36% of samples from
asymptomaticchildren.33,34 Another contradiction in theliterature
was the association of the HRVC strain with severe cases.4,5 Some
of theHRV samples we sequenced belonged tothe C strain. However,
because there wasno indication that there was an associ-ation with
disease severity, the remain-ing samples were not sequenced
(datanot shown).
CONCLUSIONS
Our results showed a high incidence ofHRVandRSVinARIs
inyoungchildren,andthemajorityof theHRV infections involvedmild
symptoms. However, we also foundHRV inmoderate tosevere cases, and
thisstudy highlighted the importance of theassociation of this
virus with coinfectionwith RSV, prematurity, congenital
heartdisease, or noninfectious respiratorydisease in symptom
severity. Also, earlyage as the only factor might not haveplayed a
role in more severe disease.These important ndings may help
chil-dren who are at higher risk of more se-vere respiratory
disease.
FIGURE 4Distribution of cases according to underlying risk
conditions in childrenup to 5 years oldwithHRVsingleinfections (N =
107). A, Age factor regardless of the presence of other
comorbidities. B, Occurrence ofeach of the comorbidities and risk
factors. The numbers shown above bars represent the corre-sponding
number of cases. P values were calculated by comparing the number
of cases in a groupwithpatients who presented with a risk factor
and a group of patients who did not present with risk factors,and
according to the severity of symptoms in each group. a Early age
exclusively. b Smoking duringpregnancy, atopic disease, anemia,
nervous system diseases, West syndrome, Down syndrome, shortbowel
syndrome, cholestatic syndrome, biliary atresia, adenomegaly, and
nodal polyarthritis.
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ACKNOWLEDGMENTSWe thank all the physicians and nurseswho helped
enroll patients in the study
and the staff who helped provide the nec-essary patient les from
the medicalarchives of the HC-UFU. We also thank
the staff members of the parasitology,physiology, and genetics
laboratories ofUFU for allowing us to use their facilities.
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(Continued from rst page)
FINANCIAL DISCLOSURE: The authors have indicated they have no
nancial relationships relevant to this article to disclose.
FUNDING: Supported by Fundao de Amparo Pesquisa do Estado de
Minas Gerais (Brazil), Conselho Nacional de Desenvolvimento Cientco
e Tecnolgico(Brazil), Coordenao de Aperfeioamento de Pessoal de
Nvel Superior (Brazil), and Pr-reitoria de Pesquisa e Ps-graduao of
Universidade Federal deUberlndia.
POTENTIAL CONFLICT OF INTEREST: Dr Costa received personal fees
from Coordenao de Aperfeioamento de Pessoal de Nvel Superior
(CAPES) and nonnancialsupport from Fundao de Amparo Pesquisa do
Estado de Minas Gerais (FAPEMIG) during the study; Dr Queirz
received grants and nonnancial support fromFAPEMIG, personal fees
and nonnancial support from Universidade Federal de Uberlndia
(UFU), nonnancial support from Fundao Instituto Oswaldo
Cruz(FIOCRUZ), and grants from Conselho Nacional de Desenvolvimento
Cientco e Tecnolgico (CNPq) during the study; Dr Lopes received
personal fees from Hospitalde Clnicas, UFU, during the study; Dr
Bernardino Neto received personal fees from CAPES; Ms Nayhanne
Tizzo de Paula received personal fees from CAPES,personal fees from
CNPq, and nonnancial support from FAPEMIG; Dr Oliveira received
nonnancial support from FAPEMIG, personal fees and nonnancial
supportfrom UFU, and nonnancial support from FIOCRUZ; Ms Tolardo
received personal fees from CNPq and nonnancial support from
FAPEMIG; and Dr Yokosawareceived nonnancial support from FAPEMIG,
nonnancial support and personal fees from UFU, and personal fees
from CNPq during the study.
ARTICLE
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DOI: 10.1542/peds.2013-2216; originally published online January
13, 2014; 2014;133;e312Pediatrics
Oliveira, Aline Lavado Tolardo and Jonny YokosawaMorun
Bernardino Neto, Nayhanne Tizzo de Paula, Thelma Ftima Mattos
Silva
Loureno Faria Costa, Divina Aparecida Oliveira Queirz, Hlio
Lopes da Silveira,Human Rhinovirus and Disease Severity in
Children
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