Abstract

Ourcurrentbedsidetestsforurinarytractinfections(UTI)arenotsufficientlyaccurate.Thebestavailabletest forUTI,theleukocyteesterase(LE)test,hasasensitivityofonly79%,meaningthat21%ofchildrenwitha trueUTIaremissed,placingthematincreasedriskforpermanentrenalscarring.The87%specificityoftheLE testmeansthat13%ofthosewithoutUTIwillbeincorrectlydiagnosedashavingUTIandreceiveantimicrobial treatment.Accordingly,developmentofmoresensitiveandspecifictestsforthediagnosisofUTI,whichisour firstaim,representsanimportantcontribution.Wewillcollecturinespecimensfrom3,334consecutivefebrile childrenaged1monthto3yearswithpresumedUTIand,inasampleofcasesandcontrolsfromthislarger population,wewillperformtranscriptomics(mRNA)andmultiplexinflammatoryproteinanalysistoidentify urinarymarkersthatdistinguishchildrenwithUTIfromfebrilechildrenwithoutUTI.Promisingmarkerswillbe validatedinasampleselectedfrom3,334childrenfromasecondsite.Asecondlimitationinthecurrentclinical approachtoUTIstemsfromthelackofreliablemarkerstodistinguishchildrenwithbladderinfectionfrom childrenwithkidneyinfection(pyelonephritis).Becauseaccuratemarkersforpyelonephritishavenotbeen identified,allfebrilechildrenwithUTIaregenerallyassumedtohavepyelonephritis(i.e.,treatedwithantibiotics for10daysandundergorenalultrasonography)eventhoughapproximatelyonly40%havepyelonephritis.To identifyaccuratemarkersforpyelonephritis,whichisoursecondaim,wewillenroll100febrilechildrenwith UTIandperformtranscriptomicsandmultiplexinflammatoryproteinanalysisontheirurinesamples. PyelonephritiswillbeconfirmedusingTc99m-dimercaptosuccinicacid(DMSA)scan.Wewillvalidate promisingmarkersinanindependentsampleof100childrenfromasecondsite.DiagnosisofUTIisespecially challenginginchildrenwithinfectionscausedbybacteriaotherthanEscherichiacoli.Accordingly,ourthirdaim willbetodeveloptestsforthediagnosisofUTIinthesechildren.Featuresthatwilldifferentiateourstudy include(1)enrollmentofconsecutivefebrilesubjects(whichwillminimizebias);?(2)useofcatheterizationto collectallurinesamples(whichwillminimizemisclassification);?(3)timelyprocessingoftheurinesamples,(4) useofanovelmethodofassemblinghigh-qualityRNAlibrariesfromsmallamountsofurine,and(5)selection ofdifferentsitesfortrainingandvalidation.Resultsfromtheproposedprojectareexpectedto(1)identifyeasy tomeasureurinaryproteinsthatcanbeusedtoaccuratelydiagnoseUTIinchildrenwithandwithoutE.coli infection,(2)developRNAsignaturesforUTIandpyelonephritiswhichcanbeusedasagoldstandardin futurestudies,and(3)establishalargespecimenbankforuseinfuturestudies.

Public Health Relevance

Thisstudywillleadtotheidentificationofbettertestsforthediagnosisofurinarytractinfections.Thisstudywill alsoidentifynewteststhatcanbeusedtodifferentiateurinarytractinfectionsinvolvingthekidneyfromurinary tractinfectionsinvolvingthebladder.Thetestsdevelopedinthisstudymayeventuallyhelpreduce inappropriateuseofantibioticswhileatthesametimereducingtheincidenceofrenalscarring.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK118033-02
Application #
9884759
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mendley, Susan Ruth
Project Start
2019-04-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260