DevelopmentandValidationofanIllnessSeverityScoringSystemforViralRespiratoryTractInfectionsinChildren

ParisaMortaji,OrrinMyers,MeganWoslager,AlfonsoBelmonte,AnnalisaBehnken,AnjaliSubbaswamy,HemantAgarwal,TeresaVigil,FrancineCaffey,MarthaMuller,DarrellDinwiddie,WalterDehority

DepartmentofPediatricInfectiousDisease,UniversityofNewMexicoSchoolofMedicine

Introduction• Viralrespiratoryinfectionsareuniversalillnessescausedbymanydifferentviralstrainsandare

highlyprevalentinyoungchildren.• Novelinvestigativetools,suchaswholegenomesequencing,offerpromiseofidentifyinggene

determinantsofdiseaseseverity,whichhelpcharacterizehostandviralgeneticcontributionstoseverityofillness.

• Avalidatedscoringsystemforquantifyingillnessseverityisneededtocontextualizeresults.• Limitationsofexistingscoringsystemsintheliterature:

• Donotreflectnovelchangesinclinicalcareovertime,suchasearlydischargerates,accesstohomehealthcare,improvedICUcare,andmedicaltechnologicaladvancement

• Limitedtoonlyoneviralseason• Fewtonoratersofdiseaseseverity• Exclusionofchildrenwithunderlyingcomorbidities• Developmentofascoringsystemforaspecificviralstrain(e.g.RSVpatientsonly)• Limitedagerangeofsubjectsandsmallsamplesizes• Frequentlycitedstudiesusedasgoldstandardsinscoringsystemdevelopmentpresented

manyoftheaforementionedlimitations• Overall:limitedgeneralizabilityandpracticality,invalidated,underpowered,andoutdated

• Anewscoringsystemthatisgeneralizableandreflectsmodernmedicalpracticeisneeded.Wesoughttodevelopsuchascoringsystemtoquantifyseverityofillnessinchildrenhospitalizedwithviralrespiratoryinfections.

Methods• Childrenhospitalizedwithviralrespiratoryinfectionswereprospectivelyenrolledovera2-year

periodfromMarch2015toMarch2017.• Childrenwererequiredtopresentwith2ofthefollowingclinicalfindingstobeeligible:

rhinorrheaornasalcongestion,cough,fever,increasedworkofbreathing,hypoxiaorsorethroat,andnoobviousalternativeetiology.

• 51clinicalvariablesfromeachsubjectwereextractedfromthemedicalrecordandenteredintoaREDCap database.

• Sevenvariablesthatsignificantlycorrelatedwitheachother(p<0.001)werecombinedintoadiseaseseverityindex:(durationofhospital/ICUstay,oxygenandhighflownasalcannula(HFNC)use,intubation,maximumnasalcannulaandHFNCoxygenrequirement).

• Forvalidationcomparison,samplingalgorithmsselectedasubsetof96patientswhosediseaseseveritywouldberandomlyassessedby8pediatriciansinblocksof12.

• Severitywasscoredonascaleof1-10.Mixedmodelregressionanalysescomparedclinician-scoreddiseaseseveritywiththescoringsystem.

• Akaike Informationcriteria(AIC)andcoefficientsofdetermination(R2)rankedseverityindices.

Conclusions• Wedevelopedanovel,validatedscoringsystemforpediatricviralrespiratoryinfections.• Toourknowledge,thisisthefirstsuchscoringindexandthelargestdatasetcomprising445

pediatricpatientswithviralrespiratoryinfections.• Thescoringindexusing7variablesand7levelsofexposureproducedanR2 of0.7atap-value

of<0.0001.Thecorrelationcoefficientof0.7,giventheinherentsubjectivityanddifficultyinvolvedindefining illnessseverity,performedandcorrelatedwellwithourclinician-assessedgoldstandard.

• Thepatientshadvariablecharacteristicsregardingageandcomorbidities,makingtheresultsmoregeneralizabletowardawiderpopulation.Inaddition,weincludedmultiplerespiratoryseasonstoallowforvariedviralvirulencebyyear,aswellasmultipledifferentvirusesandstrainswhich,again,increasesgeneralizability.

• Limitations:• Pediatricinpatientsonly• Singleinstitutioninonegeographicregionofthecountryallowsforpotentially

undetectedconfoundersanddifferingviralserovars basedonclimate,weather,andsocioeconomicfactors

• Insummary,wedevelopeda7-variablevalidateduniversalscoringindexforpediatricviralrespiratoryinfectionsforusebycliniciansandresearchers.

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AbstractNovelinvestigativetoolshelpcharacterizehostandviralgeneticcontributionstodiseaseseverityinpediatricviral

respiratoryinfections.However,avalidatedscoringsystemforquantifyingillnessseverityisneededtoproperlycontextualizeresults.Existingscoringsystemsareoutdated,invalidatedandunderpowered.Wesoughttodevelopsuchascoringsystemtoquantifyseverityofillnessinchildrenhospitalizedwithviralrespiratoryinfections.Suchascoringsystemmaybeusefultocliniciansinassessingdiseaseseverityandresearchersrequiringaquantitatedassessmentofillnessseverity.

Childrenhospitalizedwithviralrespiratoryinfectionswereprospectivelyenrolledovertwoyears(n=445),with51clinicalvariablesextractedfromthemedicalrecord.Sevenvariablesthatsignificantlycorrelatedwitheachotherwerecombinedintoadiseaseseverityindex.Foravalidationcomparison,diseaseseverityofarandomsubsetofpatientswasassessedby8pediatricians.Mixedmodelregressionanalysescomparedclinician-scoreddiseaseseveritywiththescoringsystem.AkaikeInformationcriteriaandcoefficientsofdetermination(R2)rankedseverityindices.Clinicianscoresofdiseaseseverityaveraged6.2(SD=2.2,range1-10).Ascoringsystemusing7variableswith7levelsofexposureforeachvariableproducedthelowestAIC(0.00,R2 =0.70forpredictingclinician-scoreddiseaseseverityafteradjustmentforratereffects,p<0.0001).A7-variablescoringsystemquantifyingdiseaseseverityinpediatricviralrespiratoryinfectionscorrelateswellwithclinicianassessment,andmayadvancethestudyofsuchinfections.

Results• Outof579potentialsubjectsapproached,445wereenrolled(76.9%consentrate),ofwhich

250(56.2%)weremaleand195(43.8%)werefemale.Themeanageofsubjectswas2.40years(median=1.2years,inter-quartilerange=0.4–3.2).

• Amajority(65.8%)ofsubjectshadnopastmedicalhistory.Themostfrequentmedicalproblemswereasthma(12.8%),prematurity(9.7%,definedasbirthbetween24-34weeks’gestation),andchroniclungdisease(7.6%).

• Clinicianscoresofdiseaseseverityaveraged6.2(SD=2.2,range1-10).Ascoringsystemusing7variableswith7levelsofexposurepervariableproducedthelowestAIC(0.00,R2 =0.70forpredictingclinician-scoreddiseaseseverityafteradjustmentforratereffects,p<0.0001).

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Figure1:DistributionofViral Isolates(2015– 2017)

PercentageofIsolates

Table1:RacialDemographics(n=445)

Race Number PercentWhite/Anglo 289 64.9

AmericanIndian/AlaskanNative 95 21.3

Black/AfricanAmerican 15 3.4

Asian 7 1.6

Hispanic/Latino 1 0.2

Other 3 0.7

Declinetoanswer 35 7.9

Table2:Distributionsofclinicalvariablesintotalsample(n=445)

Frequencyofpositiveclinical

values

Distributionofpositiveclinicalvalues

N (%) Median Min Max

DayswithHFNC(d) 196 (44.0) 3.0 0.1 18.9

DurationofHospitalization(d) 445 (100.0) 3.7 0.1 71.8

DurationofIntubation(d) 18 (4.0) 4.3 0.3 29.3

DurationofOxygenUseinHospital(d)

409 (91.9) 3.3 0.1 71.8

MaxHFNCRequirement(L) 200 (44.9) 12.0 3.0 35.0

MaxNasalCannulaRequirement(L) 395 (88.8) 2.0 0.1 20.0

PICUStay(d) 143 (32.1) 3.0 0.5 29.3

Table3:Results

Categoriesperclinicalvariable

r2 r2adjustedforraters p-value

3 0.499 0.671 <0.0001

4 0.461 0.662 <0.0001

5 0.486 0.680 <0.0001

6 0.483 0.684 <0.0001

7 0.509 0.700 <0.0001

8 0.491 0.687 <0.0001

9 0.480 0.685 <0.0001

10 0.484 0.691 <0.0001