DOI: 10.1542/peds.2013-1501; originally published online October 7, 2013; 2013;132;e1194Pediatrics

Piedra and Carlos A. Camargo JrErin Stucky Fisher, Besh Barcega, Ashley F. Sullivan, Janice A. Espinola, Pedro A. Alan R. Schroeder, Jonathan M. Mansbach, Michelle Stevenson, Charles G. Macias,

Apnea in Children Hospitalized With Bronchiolitis

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Apnea in Children Hospitalized With Bronchiolitis

WHAT’S KNOWN ON THIS SUBJECT: Apnea is a life-threateningcomplication of bronchiolitis and has been associated withyounger age, prematurity, and a parental report of apnea. Apneais classically attributed to the respiratory syncytial virus, but littleis known about the role of other viruses.

WHAT THIS STUDY ADDS: Among hospitalized children, low orhigh respiratory rates or low oxygen saturation on presentationwere associated with subsequent apnea in the hospital. Severalbronchiolitis pathogens were associated with apnea, with similarapnea risk across the major viral pathogens.

abstractOBJECTIVE: To identify risk factors for inpatient apnea among chil-dren hospitalized with bronchiolitis.

METHODS: We enrolled 2207 children, aged ,2 years, hospitalizedwith bronchiolitis at 16 sites during the winters of 2007 to 2010.Nasopharyngeal aspirates (NPAs) were obtained on all subjects, andreal-time polymerase chain reaction was used to test NPA samples for16 viruses. Inpatient apnea was ascertained by daily chart review,with outcome data in 2156 children (98%). Age was corrected forbirth ,37 weeks. Multivariable logistic regression was performedto identify independent risk factors for inpatient apnea.

RESULTS: Inpatient apnea was identi!ed in 108 children (5%, 95% con-!dence interval [CI] 4%–6%). Statistically signi!cant, independent pre-dictors of inpatient apnea included: corrected ages of,2 weeks (oddsratio [OR] 9.67) and 2 to 8 weeks (OR 4.72), compared with age $6months; birth weight,2.3 kg (5 pounds; OR 2.15), compared with$3.2kg (7 pounds); caretaker report of previous apnea during this bron-chiolitis episode (OR 3.63); preadmission respiratory rates of ,30 (OR4.05), 30 to 39 (OR 2.35) and.70 (OR 2.26), compared with 40 to 49; andhaving a preadmission room air oxygen saturation ,90% (OR 1.60).Apnea risk was similar across the major viral pathogens.

CONCLUSIONS: In this prospective, multicenter study of children hos-pitalized with bronchiolitis, inpatient apnea was associated withyounger corrected age, lower birth weight, history of apnea, and pre-admission clinical factors including low or high respiratory rates andlow room air oxygen saturation. Several bronchiolitis pathogens wereassociated with apnea, with similar apnea risk across the major viralpathogens. Pediatrics 2013;132:e1194–e1201

AUTHORS: Alan R. Schroeder, MD,a Jonathan M.Mansbach, MD,b Michelle Stevenson, MD,c Charles G.Macias, MD, MPH,d Erin Stucky Fisher, MD,e Besh Barcega,MD,f Ashley F. Sullivan, MS, MPH,g Janice A. Espinola, MPH,g

Pedro A. Piedra, MD,h and Carlos A. Camargo Jr, MD, DrPHg

aDepartment of Pediatrics, Santa Clara Valley Medical Center,San Jose, California; bDepartment of Medicine, Boston Children’sHospital, Harvard Medical School, Boston, Massachusetts;cDepartment of Pediatrics, University of Louisville, Louisville,Kentucky; dDepartment of Pediatrics, Section of EmergencyMedicine, Texas Children’s Hospital, Baylor College of Medicine,Houston, Texas; eDepartment of Pediatrics, Rady Children’sHospital, University of California, San Diego, San Diego,California; fDepartment of Pediatrics, Loma Linda Medical Center,Loma Linda, California; gDepartment of Emergency Medicine,Massachusetts General Hospital, Harvard Medical School,Boston, Massachusetts; and hDepartments of Molecular Virologyand Microbiology, and Pediatrics, Baylor College of Medicine,Houston, Texas

KEY WORDSapnea, bronchiolitis, viral infections, infants, hospitalization

ABBREVIATIONSCI—con!dence intervalHRV—human rhinovirusIQR—interquartile rangeNPA—nasopharyngeal aspirateOR—odds ratioPCR—polymerase chain reactionRR—respiratory rateRSV—respiratory syncytial virus

Drs Schroeder and Mansbach conceptualized and designed theinitial study, coordinated data collection at 1 of the sites, carriedout the analysis and interpretation of data, and drafted themanuscript; Drs Stephenson, Macias, Fisher, and Barcegacoordinated data collection at 1 of the sites and reviewed andrevised the manuscript; Ms Sullivan was responsible foracquisition of data and reviewed and revised the manuscript;Ms Espinola was responsible for acquisition of data, analysisand interpretation of data, and drafting of the manuscript;Dr Piedra conceptualized and designed the initial study,coordinated data collection and virology testing, carried out theanalysis and interpretation of data, and reviewed and revisedthe manuscript; Dr Camargo conceptualized and designed theinitial study, coordinated data collection for all of the sites,carried out the analysis and interpretation of data, and draftedthe manuscript; and all authors approved the !nal manuscriptas submitted.

The content of this manuscript is solely the responsibility of theauthors and does not necessarily represent the of!cial views ofthe National Institute of Allergy and Infectious Diseases or theNational Institutes of Health.

(Continued on last page)

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Apnea is a life-threatening complica-tion of bronchiolitis, the leading causeof infant hospitalization in the UnitedStates.1,2 The incidence of apnea duringbronchiolitis ranges across studiesfrom 1% to 24%,3–16 a wide range thatre"ects the use of different de!nitions(eg, variable duration of apneic period),clinical settings (eg, outpatient vs in-patient), and inclusion/exclusion crite-ria (eg, age cutoffs, comorbidities, viraletiology).

Although two-thirds of children with se-vere bronchiolitis (ie, children requiringhospitalization) have respiratory syncy-tial virus (RSV), severe bronchiolitis isassociated with multiple other viruses17

and even coinfections with multiplepathogens.17 Nonetheless previous ap-nea investigations have focused almostentirely on infants with RSV.3,5–8,16,18,19

Although evidence is sparse, apnea hasbeen reported with parain"uenza vi-rus,13 coronavirus,20 and human meta-pneumovirus.21

The current analysis is based on a largemulticenter cohort of infants hospital-ized with bronchiolitis and has the fol-lowing aims: (1) to identify independentrisk factors for theoccurrenceof apneaduring the bronchiolitis hospitalizationand (2) to compare virology results ininfants with and without apnea.

METHODS

Study Design

Weconductedaprospective,multicentercohort study for 3 consecutive yearsduring the 2007 to 2010 winter seasons,as part of the Multicenter Airway Re-search Collaboration, a program of theEmergency Medicine Network (www.emnet-usa.org). The number of partici-pating sites varied from 13 to 16 eachyear. Eachmonth from November 1 untilMarch 31, site investigators across 12US states used a standardized protocolto enroll a target number of consecutivepatients from the inpatient wards and

the ICU. We aimed to enroll 20% of ourtotal sample from the ICU. To over-sample children from the ICU, the wardand ICU enrollments were monitoredseparately. Once the site teams reachedtheir target enrollment for each month,enrollment stopped until the beginningof the next month.

All patientswere treated at the discretionof the treating physician. Inclusion cri-teria were an attending physician’s di-agnosis of bronchiolitis, age ,2 years,and the ability of the caretaker to giveinformed consent. Patientswere enrolledwithin 18 hours of admission. Exclusioncriteria were transfer to a participatinghospital .48 hours after the originaladmission time or previous enrollment(although data from the initial hospi-talization for previously enrolled pa-tients were still included). Patientswithcomorbidities were not excluded. Theconsent and data collection formswere translated into Spanish. The in-stitutional review board at all partici-pating hospitals approved the study.

Data Collection

Investigators conducted a structuredinterview with the children’s caretakersthat assessed patients’ demographiccharacteristics, medical and environ-mental history, duration of symptoms,and details of the acute illness. Thestructured interview included the ques-tion, “Has [child] stopped breathingduring this illness?” For the remainderof the article, we use the term “reportedapnea” for this variable. Medical re-cords were reviewed to obtain clinicaldata from the preadmission evaluation(clinic or emergency department) andthe child’s inpatient course, includingrespiratory rates (RR), daily respi-ratory rate trends, clinical assessmentof degree of retractions, oxygen satu-ration, daily oxygen saturation trends,medical management, and disposition.These data were manually reviewedat the Emergency Medicine Network

Coordinating Center and site investi-gators were queried about missingdata and discrepancies identi!ed bythese manual data checks.

To examine inpatient apnea amongchildren admitted to the hospital withbronchiolitis, we identi!ed all childrenwho experienced apnea at any timeduring their hospitalization. Every daya child was in the hospital, site inves-tigators examined the medical recordsof each participant for documentationof apnea. The site investigators com-pleted the daily chart reviews byresponding to the question: “Has pa-tient experienced apnea?” Among the2207 enrolled subjects, 2156 (98%) hadinpatient apnea status reported. Miss-ing data were attributed to having nodaily inpatient form available (n = 31,1.4%) or no response to the inpatientapnea question on any daily inpatientforms (n = 20, 0.9%).

Nasopharyngeal AspirateCollection and Virology Testing

NPAs were performed by using a stan-dardized protocol. Designated sitepersonnel were trained by using a lec-ture, written instructions, and video.All of the sites used the same collec-tion equipment (Medline Industries,Mundelein, IL) and collected 98% of thesamples within 24 hours of a child’sarrival on the medical ward or ICU.Once collected, the NPA sample wasadded to transport medium, placed onice, and then stored at –80°C. Frozensamples were batch shipped overnighton dry ice to the central laboratory atBaylor College of Medicine, where theywere stored at –80°C.

Polymerase Chain Reaction Assay

All polymerase chain reaction (PCR)assayswere conducted as singleplex orduplex 2-step real-time PCR. Real-timereverse transcriptase-PCR was usedfor the detection of RNA and DNA re-spiratory viruses, which included RSV

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types A and B; human rhinovirus (HRV);parain"uenza virus types 1, 2, and 3;in"uenza virus types A andB; 2009 novelH1N1; human metapneumovirus; coro-naviruses NL-63, HKU1, OC43, and 229E;enterovirus; and adenovirus. Myco-plasma pneumoniae and Bordetellapertussis were also sought by real-time PCR. Details of the primers andprobes have been described else-where.22–24All real-time PCR assayswere tested in duplicate and sampleswith incongruent values (1 well posi-tive) were retested. To reduce carry-over contamination, sample preparation,RNA/DNA extraction, cDNA, and ampli-!cation were performed in separateareas. All PCR runs had extraction andreagent positive and negative controls.

Statistical Analyses

All analyses were performed by usingStata 11.2 (Stata Corp, College Station,TX). Data are presented as proportionswith 95% con!dence intervals (CIs) andmedians with interquartile ranges(IQR). To examine potential risk factorsfor apnea among patients hospitalizedfor bronchiolitis, we initially performedunadjusted analyses using x2, Fisher’sexact test, and Kruskall-Wallis test, asappropriate. All P values were 2-tailed,with P , .05 considered statisticallysigni!cant.

Multivariable logistic regression wasconducted to evaluate independentpredictors of inpatient apnea. Factorswere tested for inclusion in themodel ifthey were found to be associated withthe outcome in unadjusted analyses(P, .20) or were considered potentiallyclinically signi!cant. To prevent theexclusion of children who were miss-ing race data (9%) and to minimize thenumber of included factors that wereunassociated with inpatient apnea,race was dichotomized as white versusnonwhite/missing. Sensitivity analyseswere performed using a 3-categoryversion of the race variable (ie, white,

nonwhite, and missing), but results didnot materially differ compared withwhen using the dichotomized version(data not shown).

For all children born prematurely(gestational age ,37 weeks), age wascorrected by subtracting the numberof weeks the child was premature fromthe chronologic age. More speci!cally,for a child with a gestational age ,37weeks, their corrected age was calcu-lated by using the formula: chronolog-ical age – (37 – gestational age) =corrected age. The !nal regressionmodel accounts for potential cluster-ing by site, with results reported asodds ratios (ORs) with 95% CIs.

RESULTS

Overall, the median age of the 2156children in the analysis cohort was 4months (IQR, 2–9 months), 59% wereboys, and 62% were white. Admissionlocations were as follows: ICU (16%),step-down unit (3%), ward (76%), andobservation unit (5%).

During their inpatient stay, 108 infants(5%; 95% CI, 4%–6%) had documentedapnea. Of these cases, 56 (52%) weremanaged at some point during thehospitalization in the ICU, and 30 (28%)received mechanical ventilation (ie,continuous positive airway pressureand/or intubation). The majority (78%)of infants with inpatient apnea were!rst observed to have apnea within the!rst 2 days of hospitalization. However,3 patients (3%) had apnea as late as 13days into their hospital stay. Moreover,86 (80%) children had only 1 hospitalday with recorded apnea, 13 (12%) hadapnea on 2 days, and 9 (8%) had apneaon .2 days (max = 4 days).

Unadjusted associations between de-mographic and clinical characteristicsand inpatient apnea during the in-patient stay are presented in Tables 1and 2. Infants with apnea were morelikely to require ICU admission during

the hospital stay (52% vs 16%, P ,.001) and to have longer median lengthof stay (4 days vs 2 days, P , .001)compared with infants who did nothave apnea. The multivariable logisticregression model for inpatient apneais shown in Table 3. Independent riskfactors included corrected age ,2weeks, birth weight,2.3 kg (5 pounds),reported apnea, low (,30 and 30–39)and high (.70) respiratory rates andoxygen saturation ,90% during thepreadmission visit. The independentrisk factor with the largest OR for ap-nea during the hospital stay was cor-rected age ,2 weeks (OR 9.67, 95% CI4.11–22.75). However, 17 (16%) infantswith apnea had a corrected age of$6 months. Results from a sensitivityanalysis that excluded these olderchildren did not materially differ fromresults presented herein using all 2156children (data not shown).

To examine whether premature birth,37 weeks and chronological agewere independent predictors of apnea,we ran a second model that used thesevariables instead of the corrected agevariable. In addition, due to the collin-earity between prematurity and birthweight, birth weight was removed fromthis second model. In this model, youngage (,1 month: OR 5.16, 95% CI 2.13–11.49; 1–1.9 months: OR 3.88, 95% CI1.95–7.71 compared with $6 months)and prematurity (OR 2.44, 95% CI 1.46–4.09) were both independently associ-ated with apnea, and other predictorsdid not differ materially from themodel presented in Table 3.

Two hundred seventy-eight (13%, 95%CI 12%–14%) children had parent-reported apnea before admissionduring the current bronchiolitis epi-sode. On multivariable analysis, pre-vious apnea was an independent riskfactor for inpatient apnea (OR 3.63, 95%CI 2.55–5.16). However, most children(59%) with previous apnea did not ex-perience apnea while hospitalized.

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Infantswith andwithout inpatient apneahad similar viruses identi!ed (Fig 1). Forexample, RSV was common amonginfants with and without apnea (78% vs72%, P = .16) as was HRV (24% vs 26%,P = .71). The number of patients infectedwith viruses besides RSV and HRV waslow when strati!ed by apnea status.However, adenovirus was isolatedslightly less frequently in infants withapnea (3% vs 8%, P = .04). For thoseviruses with multiple subtypes (RSV, in-"uenza, parain"uenza, and coronavi-rus), there was no association betweenthe viral subtype and apnea risk. Infantswith viral coinfections (ie,.1 virus) hada similar frequency of apnea compared

with infants who had only 1 virus iden-ti!ed (4% vs 6%, P = .08).

Infants with apnea were signi!cantlyless likely to have been exposed toseveral therapeutic agents (antibiotics,acetaminophen, and bronchodilators)during the week before admission andwere less likely to have attended daycare (Table 1). However, on multivari-able analysis, none of these associa-tions were statistically signi!cant.

DISCUSSION

In this prospective, multicenter study ofapnea among infants hospitalized withbronchiolitis, we not only con!rmed

severalpreviously reportedrisk factorsfor apnea (eg, young corrected age, lowbirth weight, and reported apnea) butalso identi!ed several novel pread-mission risk factors including a low orhigh RR and a low room air oxygensaturation. Moreover, we found thatmultiple viruses were associated withapnea, with similar apnea risk acrossthe major viral pathogens.

Inpatient apnea occurred in 5% of thehospitalized children in our bronchiolitiscohort. In one of the few other large,prospective investigations, Hall andcolleagues found that apnea occurredin 1% of 561 children hospitalized withRSV infection. This study, however, in-cluded not only children aged#5 yearsbut also children without bronchioli-tis.7 A more recent prospective, multi-center investigation of 1306 infantspresenting to an emergency depart-ment with RSV infection (bronchiolitis,pneumonia, or apnea) reported apneain 21 (1.6%) children.8 The higher in-cidence in our data are most likely dueto our population (severe bronchiolitis)and the fact that we oversampledchildren admitted to the ICU. Nonethe-less, our reported incidence of 5% islower than the 10% to 20% incidencerates based on populations of young(,6–12 months) and/or prematureinfants hospitalized with RSV bron-chiolitis.5,6,14,15 It is also possible thatthe administration of RSV immunopro-phylaxis to vulnerable populations hasled to a decrease in the overall in-cidence of apnea.

We con!rmed several risk factors forapnea including young corrected age,low birthweight, and reported apnea. Ina retrospective study of 691 infants hos-pitalized with bronchiolitis, Willwerthand colleagues13 found that the 19 (3%)children with apnea in their cohort allhad $1 of the following character-istics: age ,1 month, born at ,37weeks gestation and ,48 weeks post-conception, and a witnessed apneic

TABLE 1 Demographic Characteristics and Medical History of Children With Bronchiolitis byInpatient Apnea Status

Characteristics n No Apnea(n = 2048), %

Apnea(n = 108), %

P

HistoryAge, corrected for gestational age ,37 wk ,.001,2.0 wk 81 3 162.0–7.9 wk 531 23 462.0–5.9 mo 786 37 22$6.0 mo 758 36 16

Gender .23Male 1278 60 54Female 878 40 46

Race .77White 1372 62 60Nonwhite or missing 829 38 40Hispanic 781 36 37 .86

Birth wt .001,2.3 kg (5 lb) 274 12 222.3–3.1 kg (5–6.9 lb) 747 35 41$3.2 kg (7 lb) 1110 53 36

Any comorbidity 454 21 19 .55Breast fed 1303 61 56 .28Attends day care 405 19 7 .001Maternal smoking during pregnancy 325 15 20 .19Secondhand smoke exposure 277 13 15 .54Reported apnea 278 12 41 ,.001Time dif!culty breathing began before preadmission visit .53None 47 2 2,24 h 580 27 271–3 d 913 43 374–7 d 444 21 25.7 d 143 7 9

Exposure to therapeutics within the week preceding the clinicvisitBronchodilators 816 39 23 .001Inhaled/nebulized steroids 170 8 8 .87Systemic steroids 232 11 10 .90Acetaminophen 1151 56 38 ,.001Antibiotics 414 20 11 .03

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event by either the parent or theemergency department clinician be-fore inpatient admission. Birth weightwas not included as a risk criterion.The positive predictive value was 7%,re"ecting the low overall incidence ofapnea and the low speci!city of theserisk factors. Interestingly, none of the672 children without apnea had 1 ofthese characteristics, resulting in anegative predictive value of 100%.

One of the novel !ndings in our analysiswas the U-shaped association betweenthe preadmission RR and apnea. Inotherwords, childrenwith initial lowRR(,30 and 30–39) or high RR (.70) hada higher risk of apnea than infants withan initial RR between 40 and 70. To ourknowledge, an association betweeninitial RR and apnea has not beenpreviously described, and there is noclear explanation for these novel !nd-ings. Although clinicians would con-sider children with bronchiolitis anda RR .70 as ill, a RR of ,30 or 30–39may be falsely reassuring. However, itis comforting to remember that all ofthe children in this cohort were hos-pitalized and therefore judged to be illenough for hospitalization by the ad-mitting clinician. Furthermore, thesedata require validation in a differentstudy of children with bronchiolitis.

Infants with a preadmisison oxygensaturation ,90% were also at higherrisk for apnea. Although the patho-physiology of apnea is unclear, Anasand colleagues3 found that 5 infantswith apnea had a higher alveolar-arterial gradient than 27 infants with-out apnea (170 vs 45 mm Hg, P , .01).Although others have not found an as-sociation between oxygenation andapnea,6,13 we had a larger sample sizeand recorded oxygen saturation atboth triage and throughout the pre-admission visit. This methodology mayhave enabled us to identify this riskfactor. Given that low pulse oximetryvalues are already used as a criterion

TABLE 2 Preadmission Clinical Presentation of Children With Bronchiolitis by Inpatient ApneaStatus

Clinical Characteristics n No Apnea(n = 2048), %

Apnea(n = 108), %

P

Apnea (preadmission chart review) 152 5 41 ,.001Respiratory rate, median (IQR) 2135 48 (40–60) 44 (36–60) .07Respiratory rate .01,30 121 5 1230–39 389 18 2340–49 655 31 2250–59 358 17 1560–69 394 19 14$70 218 10 13

Retractions .001None 472 21 33Mild 901 42 29Moderate/severe 633 30 26Missing 150 7 12

OxygenationInitial oxygen saturation, median (IQR) 2109 96 (93–98) 97 (92–99) 1.00Initial oxygen saturation ,90% 247 11 20 .004Lowest documented oxygen saturation, median (IQR) 2119 93 (89–96) 92 (85–96) .03Lowest documented oxygen saturation ,90% 612 28 41 .01

Oral intake .004Adequate 928 44 28Inadequate 923 42 56Missing 305 14 17

IV line placed 1218 56 73 .001Any laboratory tests 1887 88 94 .08

IV, intravenous.

TABLE 3 Multivariable Model of Factors Associated With Inpatient Apnea Among ChildrenAdmitted to the Hospital With Bronchiolitis

Characteristics OR 95% CI P

Age, corrected for gestational age ,37 wk,2.0 wk 9.67 4.11–22.75 ,.0012.0–7.9 wk 4.72 2.30–9.68 ,.0012.0–5.9 mo 1.47 0.68–3.19 .33$6.0 mo 1.00 Reference

GenderMale 1.00 ReferenceFemale 1.12 0.78–1.61 .53

RaceWhite 1.00 ReferenceNonwhite or missing 1.28 0.70–2.36 .42

Birth wt,2.3 kg (5 lb) 2.15 1.18–3.92 .012.3–3.1 kg (5–6.9 lb) 1.54 0.94–2.53 .09$3.2 kg (7 lb) 1.00 Reference

Reported apnea 3.63 2.55–5.16 ,.001Respiratory rate at preadmission visit,30 4.05 2.00–8.20 ,.00130–39 2.35 1.52–3.64 ,.00140–49 1.00 Reference50–59 1.29 0.66–2.51 .4660–69 1.06 0.62–1.81 .84$70 2.26 1.03–4.95 .04

Lowest documented oxygen saturation over entire preadmissionvisit ,90%

1.60 1.03–2.46 .04

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for hospitalization and supplementaloxygen,22,23 this !nding may not affectclinical practice.

Our virology results demonstrate thatmany viruses are associated with in-patient apnea during the bronchiolitishospitalization. Multiple previous inves-tigations of apnea associated with viralinfections have focused exclusively onRSV, and several sources have perpet-uated the notion that RSV speci!callyshould heighten concerns of apneain comparison with other viruses.5,24

However, according to our data, therisk of apnea does not signi!cantlydiffer in infants with RSV and non-RSVbronchiolitis. These data suggest thatusing RSV status to drive admissiondecisions and admission locations (eg,ward, step-down unit, ICU) due to ap-nea concerns may be misguided. Sup-porting the lack of an associationbetween virology and apnea is the!nding that viral etiology was notlinked with the acute severity of bron-chiolitis (as measured by initial ad-mission to ICU or the use of mechanicalventilation) in this same cohort. How-

ever, it should be noted that we did !ndan association between viral etiologyand hospital length of stay.17

Exposure to various therapeutic agents(antibiotics, acetaminophen, and bron-chodilators) during the week beforeadmission appeared to have a “pro-tective” association against apnea inunadjusted analyses. On multivariableanalysis, however, none of these medi-cations remained statistically signi!-cant, thereby con!rming the presenceof$1 confounding factors. Even thougha recent study of 42 infants with ap-nea concluded that acetaminophen wasprotective against apnea,25 we cautionagainst using acetaminophen for thispurpose; based on a much larger sam-ple, our data do not support this in-ference.

The time course of apnea in bronchio-litis is not well understood. In previousstudies, apnea has been described tooccur early in the course of RSV in-fection.3,26 Our results challenge thisnotion. Approximately one-third of theinfants with apnea in our study beganhaving “dif!culty breathing” $4 days

before the preadmission visit. Fur-thermore, the time from the beginningof the “dif!culty breathing” to the pre-admission visit was not different be-tween children with andwithout apnea.Therefore, using the duration ofsymptoms to predict future risk of ap-nea or need for hospitalization may beproblematic.

Our study has several potential limi-tations. Although it was a large, pro-spective study that required dailyrecording of the presence of apnea, thereported incidence of apnea (5%) maybe biased by several factors. First,sicker patients were oversampled be-cause we aimed to enroll 20% of oursample from the ICU. Second, subjectswere considered to have apnea if therewas documentation in the chart thatapnea had occurred, so some infantsmay have been included who did notmeet strict criteria for apnea (eg,cessation of breathing for at least 20seconds4,10). Alternatively, apnea mayhave been more challenging to detectin intubated patients leading to un-derreporting in this population. Last,

FIGURE 1Viral pathogens isolated in infants with and without apnea. HMPV, human metapneumovirus; PIV, parain"uenza virus.

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bronchiolitis is a clinical diagnosis.22

As a result, the site teams may haveincluded children who did not havebronchiolitis or missed children whopresented with apnea22 and were di-agnosed with an acute life-threateningevent27 or “apnea” instead of bronchi-olitis. Nonetheless, this is the largestprospective study of apnea in childrenwith bronchiolitis and included datafrom 16 hospitals across the UnitedStates.

CONCLUSIONS

In these prospective, multiyear, multi-center data, we found several historicaland clinical factors associated withapnea among children hospitalizedwith bronchiolitis. The association be-tween low respiratory rates and apneaprovides cautionary data to practi-tioners feeling reassured by lower RR.Moreover, the !nding that multipleviruses are associatedwith apnea, with

similar apnea risk across the majorviral pathogens, suggests possiblechanges in clinicians’ practice. Our!ndings do not support the practice ofusing virology results to drive man-agement decisions involving infantswith apnea or the potential for apnea.

ACKNOWLEDGMENTSThe Principal Investigators at the 16 Par-ticipating Sites were as follows: BeshBarcega, MD, Loma Linda UniversityChildren’s Hospital (Loma Linda, CA);John Cheng, MD and Carlos Delgado,MD, Children’s Healthcare of Atlanta atEgleston (Atlanta, GA); Dorothy Damore,MD and Nikhil Shah, MD, New YorkPresbyterian Hospital (New York, NY);Haitham Haddad, MD, Rainbow Babies& Children’s Hospital (Cleveland, OH);Paul Hain, MD and Mark Riederer, MD,Monroe Carell Jr. Children’s Hospital atVanderbilt (Nashville, TN); Frank LoVe-cchio, DO, Maricopa Medical Center

(Phoenix, AZ); Charles Macias, MD,MPH, Texas Children’s Hospital (Houston,TX); Jonathan Mansbach, MD, BostonChildren’s Hospital (Boston, MA); EugeneMowad, MD, Akron Children’s Hospital(Akron, OH); Brian Pate, MD, Children’sMercy Hospital & Clinics (Kansas City,MO); M. Jason Sanders, MD, Children’sMemorial Hermann Hospital (Houston,TX); Alan Schroeder, MD, Santa ClaraValley Medical Center (San Jose, CA);Michelle Stevenson, MD, MS KosairChildren’s Hospital (Louisville, KY); ErinStucky Fisher, MD, Rady Children’s Hos-pital (San Diego, CA); Stephen Teach, MD,MPH, Children’s National Medical Center(Washington, DC); and Lisa Zaoutis,MD, Children’s Hospital of Philadelphia(Philadelphia, PA).

We thank the Multicenter Airway Re-search Collaboration-30 investigatorsfor their ongoing dedication to bron-chiolitis research.

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(Continued from !rst page)

www.pediatrics.org/cgi/doi/10.1542/peds.2013-1501

doi:10.1542/peds.2013-1501

Accepted for publication Aug 22, 2013

Address correspondence to Alan Schroeder, MD, Department of Pediatrics, Santa Clara Valley Medical Center, 751 S Bascom Ave, San Jose, CA 95128. E-mail: Alan.Schroeder@hhs.sccgov.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no !nancial relationships relevant to this article to disclose.

FUNDING: Supported by grants U01 AI-67693 and K23 AI-77801 from the National Institutes of Health (Bethesda, MD). Funded by the National Institutes of Health(NIH).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential con"icts of interest to disclose.

ARTICLE

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DOI: 10.1542/peds.2013-1501; originally published online October 7, 2013; 2013;132;e1194Pediatrics

Piedra and Carlos A. Camargo JrErin Stucky Fisher, Besh Barcega, Ashley F. Sullivan, Janice A. Espinola, Pedro A. Alan R. Schroeder, Jonathan M. Mansbach, Michelle Stevenson, Charles G. Macias,

Apnea in Children Hospitalized With Bronchiolitis

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