jurnal pediatrics 2014

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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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.


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.


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.


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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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


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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