Document text
Assessment of 135 794 Pediatric Patients Tested for Severe Acute
Respiratory Syndrome Coronavirus 2 Across the United States
L. Charles Bailey, MD, PhD; Hanieh Razzaghi, MPH; Evanette K. Burrows, MPH; H. Timothy Bunnell, PhD; Peter E. F. Camacho, MS;
Dimitri A. Christakis, MD, MPH; Daniel Eckrich, MLIS; Melody Kitzmiller, BS; Simon M. Lin, MD, MBA; Brianna C. Magnusen, MD;Jason Newland, MD; Nathan M. Pajor, MD, MS; Daksha Ranade, MPH, MBA; Suchitra Rao, MD, MSCS; Olamiji Sofela, MBChB, MMCi;Janet Zahner, BS; Cortney Bruno, MSW; Christopher B. Forrest, MD, PhD
IMPORTANCE
There is limited information on severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) testing and infection among pediatric patients across the United States.
OBJECTIVE To describe testing for SARS-CoV-2 and the epidemiology of infected patients.
DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted using
electronic health record data from 135 794 patients younger than 25 years who were tested
for SARS-CoV-2 from January 1 through September 8, 2020. Data were from PEDSnet,a network of 7 US pediatric health systems, comprising 6.5 million patients primarily from11 states. Data analysis was performed from September 8 to 24, 2020.
EXPOSURE Testing for SARS-CoV-2.
MAIN OUTCOMES AND MEASURES SARS-CoV-2 infection and coronavirus disease 2019
(COVID-19) illness.
RESULTS A total of 135 794 pediatric patients (53% male; mean [SD] age, 8.8 [6.7] years; 3%
Asian patients, 15% Black patients, 11% Hispanic patients, and 59% White patients; 290 per10 000 population [range, 155-395 per 10 000 population across health systems]) were testedfor SARS-CoV-2, and 5374 (4%) were infected with the virus (12 per 10 000 population [range,7-16 per 10 000 population]). Compared with White patients, those of Black, Hispanic, and Asianrace/ethnicity had lower rates of testing (Black: odds ratio [OR], 0.70 [95% CI, 0.68-0.72];Hispanic: OR, 0.65 [95% CI, 0.63-0.67]; Asian: OR, 0.60 [95% CI, 0.57-0.63]); however, theywere significantly more likely to have positive test results (Black: OR, 2.66 [95% CI, 2.43-2.90];Hispanic: OR, 3.75 [95% CI, 3.39-4.15]; Asian: OR, 2.04 [95% CI, 1.69-2.48]). Older age (5-11 years:OR, 1.25 [95% CI, 1.13-1.38]; 12-17 years: OR, 1.92 [95% CI, 1.73-2.12]; 18-24 years: OR, 3.51 [95% CI,3.11-3.97]), public payer (OR, 1.43 [95% CI, 1.31-1.57]), outpatient testing (OR, 2.13 [1.86-2.44]),and emergency department testing (OR, 3.16 [95% CI, 2.72-3.67]) were also associated withincreased risk of infection. In univariate analyses, nonmalignant chronic disease was associatedwith lower likelihood of testing, and preexisting respiratory conditions were associated withlower risk of positive test results (standardized ratio [SR], 0.78 [95% CI, 0.73-0.84]). However,several other diagnosis groups were associated with a higher risk of positive test results:malignant disorders (SR, 1.54 [95% CI, 1.19-1.93]), cardiac disorders (SR, 1.18 [95% CI, 1.05-1.32]),endocrinologic disorders (SR, 1.52 [95% CI, 1.31-1.75]), gastrointestinal disorders (SR, 2.00[95% CI, 1.04-1.38]), genetic disorders (SR, 1.19 [95% CI, 1.00-1.40]), hematologic disorders(SR, 1.26 [95% CI, 1.06-1.47]), musculoskeletal disorders (SR, 1.18 [95% CI, 1.07-1.30]), mentalhealth disorders (SR, 1.20 [95% CI, 1.10-1.30]), and metabolic disorders (SR, 1.42 [95% CI,1.24-1.61]). Among the 5374 patients with positive test results, 359 (7%) were hospitalized forrespiratory, hypotensive, or COVID-19–specific illness. Of these, 99 (28%) required intensive careunit services, and 33 (9%) required mechanical ventilation. The case fatality rate was 0.2%(8 of 5374). The number of patients with a diagnosis of Kawasaki disease in early 2020 was 40%lower (259 vs 433 and 430) than in 2018 or 2019.
CONCLUSIONS AND RELEVANCE In this large cohort study of US pediatric patients, SARS-CoV-2
infection rates were low, and clinical manifestations were typically mild. Black, Hispanic, and
Asian race/ethnicity; adolescence and young adulthood; and nonrespiratory chronic medical
conditions were associated with identified infection. Kawasaki disease diagnosis is not an
effective proxy for multisystem inflammatory syndrome of childhood.
JAMA Pediatr. 2021;175(2):176-184. doi:10.1001/jamapediatrics.2020.5052
Published online November 23, 2020.Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: L. Charles
Bailey, MD, PhD, Department of
Pediatrics, Children’s Hospital of
Philadelphia, 2716 South St,
11th Floor, Philadelphia, PA 19146
([email protected]).Research
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Thenovelsevereacuterespiratorysyndromecoronavi-
rus2(SARS-CoV-2)emergedinNovember2019andbyMarch2020waspandemic.
1Reportedcasesofcorona-
virusdisease2019(COVID-19)haveexceeded8.5millionintheUnitedStates
2andaredeclininginsomeregionsandrisingin
others.3Althoughseveralsyndromicpresentationshavebeen
reported,thereisalackofsystematicinformationdocument-ing the effects of SARS-CoV-2 on children, adolescents, andyoungadults.
Pediatric patients account for a disproportionately small
number of reported cases of COVID-19.
4-6The Centers for
Disease Control and Prevention noted that, although 23% ofthe US population is younger than 18 years, 2% of cases ofCOVID-19 occurring between February 12 and April 2, 2020,wereinthepediatricpopulation.
7Inaseriesof2135pediatric
casesinChina,51%weremild.8Asymptomaticpediatriccases
of COVID-19 have also been documented,8-10and because
asymptomatic patients are not routinely tested, the full ex-tentofSARS-CoV-2infectionandCOVID-19illnessinthepe-diatric population has been underrepresented in epidemio-logicstudies.
The role of chronic medical conditions in disease sever-
ity remains a major concern. A retrospective study of 177childrenfoundthat63%ofthosehospitalizedwithCOVID-19hadunderlyingconditions,comparedwith32%ofnonhospi-talized patients with COVID-19, and 78% of critically ill chil-dren with COVID-19 had underlying conditions comparedwith 57% of hospitalized, non–critically ill patients withCOVID-19.
11In a report on 48 patients with COVID-19 in the
pediatric intensive care unit, nearly all (83%) had underlyingconditions.
12TheUSCentersforDiseaseControlandPreven-
tion has noted that, in a series of 295 children with COVID-19, a much higher percentage (77%) who were hospitalizedhadanunderlyingconditionthanthosewhowerenothospi-talized (12%).
7
In addition to respiratory illness, concerns have arisen
around multisystem inflammatory syndrome in children(MIS-C).
13An Italian series of 10 cases of Kawasaki-like syn-
drome included 8 patients with antibodies againstSARS-CoV-2.
14NewYorkstatehasreportedmorethan100cases
ofKawasaki-likedisease,including3deaths,amongchildrenwithCOVID-19.
15OurevolvingknowledgeofMIS-Csuggests
that available evidence may be revealing only a partial pic-tureoftheeffectofCOVID-19inthepediatricpopulation.
Most information about pediatric COVID-19 arises from
single institutions and international studies. We report herethe multicenter experience of 7 large pediatric health sys-temsinPEDSnet( https://pedsnet.org),acollaborativelearning
healthnetworkthatsharesinpatientandoutpatientelectronichealthrecorddataforallpatientsandconductsresearchandoutcomes improvement, as well as contributes to initiativessuch as OHDSI (Observational Health Data Sciences andInformatics [https://www.ohdsi.org]) and PCORnet (theNational Patient-Centered Clinical Research Network[https://pcornet.org]).
16,17PEDSnetinstitutionsprovidecarefor
both healthy pediatric patients and those with medicallycomplexconditions.WedescribetheuseoftestingforSARS-CoV-2 across the network through September 8, 2020, anddescribe patient characteristics associated with testing andinfection.
Methods
Human Participant Research
Extraction and transformation of data for PEDSnet, includingremoval of direct identifiers, proceeded with oversight of in-stitutional review boards at each institution, which deter-minedthatwaiverofconsentandHealthInsurancePortabilityandAccountabilityActauthorizationwererequiredowingtoim-practability. The Children’s Hospital of Philadelphia institu-tional review board reviewed the analyses reported here anddeterminedthattheydidnotconstitutehumanparticipantre-search. Reporting of study design and results follows theStrengthening the Reporting of Observational Studies in Epi-demiology (STROBE) reporting guideline for observationalresearch.
18
Study Setting
PEDSnet institutions participating include Children’s Hospi-talofPhiladelphia,CincinnatiChildren’sHospitalMedicalCen-ter(testedpatientsonly),Children’sHospitalofColorado,Na-tionwide Children’s Hospital, Nemours Children’s HealthSystem(aDelawareandFloridahealthsystem),SeattleChil-dren’s Hospital, and St Louis Children’s Hospital. Annually,PEDSnetinstitutionsprovideservicestoabout3%ofthena-tion’schildren(2.5millionpatients).
PEDSnet Viral Illness Group
Since March 2020, PEDSnet institutions have implementedrapid data refreshes of data describing patients who were (1)tested for infection using reverse transcriptase–polymerasechainreactionforSARS-CoV-2,(2)assignedadiagnosiscodeforCOVID-19illness,or(3)assignedadiagnosiscodeforviralillness,respiratoryinfection,orfever(collectivelyreferredtoastheinclusiondiagnosis)(eTable1intheSupplement).
19All
historicaldatawereextractedforpatientswhometinclusioncriteriaandwerestandardizedtothePEDSnetcommondataKey Points
Question What is the epidemiology across the United States of
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection among pediatric patients undergoing diagnostic testingfor the virus?
Findings In this cohort study using electronic health records for
135 794 US pediatric patients in 7 children’s health systems,
96% of patients tested had negative results, and rates of severecardiorespiratory presentation of coronavirus disease 2019(COVID-19) illness were low. Minority race/ethnicity, chronicillness, and increasing age were associated with SARS-CoV-2infection.
Meaning This study suggests that for most pediatric patients,
the risk of SARS-CoV-2 infection appears low, but higher concern
may be warranted for patients with medically complex conditionsor those of minority race/ethnicity.Assessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States Original Investigation Research
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model, an extension of the OMOP (Observational Medical
Outcomes Partnership) common data model, describedelsewhere.
16,20,21Institutionsvalidatedthecountoftestedpa-
tientsandpatientswithpositivetestresultswithinternalreg-istries.ThisreportusesthedataextractoccurringfromJanu-ary1throughSeptember8,2020.
Withinthisgroup,recentpatientsarethosewithatleast1
diagnosisbetweenJuly1,2018,andDecember31,2019(ie,18monthsbeforethestudy’sobservationperiod),andwereusedas the denominator for testing rates. Recurring patients hadatleast2visitsinthe3yearsbeforethetimeofinclusion,andare used as the denominator for analyses including chronicmedicalconditions.
Cohort Formation
Includedpatientswereyoungerthan25yearspriortoMarch1, 2020; this age was selected based on institutional policiesfor the transition of patients to adult care, and reflects na-tionaltrendsextendingpediatriccareintoearlyadulthood.
22,23
Patient characteristics and health care use were recorded inthe electronic health record according to institutional prac-tice. Tested patients were subdivided into those with posi-tive results without severe illness, positive results with se-vereillness,andnegativetestresults.Ifapatienthadmultipletest results, they were classified as positive if any reversetranscriptase–polymerasechainreactiontestresultwasposi-tiveoraserologictestresultwaspositiveandnonegativere-verse transcriptase–polymerase chain reaction results werepresent.Severeillnesswasdefinedashospitalizationnoear-lier than 7 days prior to the testing date and an inpatient di-agnosisofpneumonia,sepsis,respiratoryfailure,orCOVID-19(eTable 2 in the Supplement). Demographic and clinical fea-tureswerecomparedacrossthe3groups.
Health Care Use
Hospitaladmissionwasdefinedasaninpatientvisitextend-ingacross2calendardays,anemergencydepartment(ED)visitatasitedesignatedbythehealthsystemasanED,andanout-patient visit as any other in-person visit. Intensive care unitadmission was defined as the presence of an admission ortransfereventtoanintensivecareunitintheelectronichealthrecord. Mechanical ventilation was established by docu-mented use of continuous positive airway pressure, bilevelpositiveairwaypressure,oramechanicalventilator;2ormoreentrieswererequired.
Health Conditions
WeusedthetaxonomyfromthePediatricMedicalComplex-ity Algorithm (PMCA),
24,25which uses International Statisti-
calClassificationofDiseasesandRelatedHealthProblems,TenthRevision, Clinical Modification (ICD-10-CM) codes to aggre-
gaterelatedchronicdiagnosesaccordingtobodysystem,witha separate category for malignant neoplasms. A condition isconsidered progressive if it is associated with deterioratinghealthandincreasedriskofshortenedlifeexpectancyinadult-hood.Forourexaminationofbaselinechronicconditions,weconsidered only diagnoses occurring prior to March 1, 2020,andlookingback3yearsfromthedateofthetest(whenavail-able)orlastrecordeddiagnosis(forcomparisongroups),tore-moveanyeffectofCOVID-19.Fortheseanalyses,werequiredthatpatientsmeettherecurringpatientcriteriatoensurethatadequatehistorywasavailable.Obesitywasdefinedaspres-enceofanage-andsex-standardizedbodymassindex zscore
inthe95thpercentileorhigherforpatientsaged2to20years,or body mass index of more than 30 (calculated as weight inkilograms divided by height in meters squared) for patientsaged21to24years,basedonheightandweightmeasuredin2020. Specific conditions (eg, diabetes and asthma) wereidentified using Systematized Nomenclature of Medicine–ClinicalTerms(SNOMED-CT)terms.
26
Kawasaki Estimation
Multisystem inflammatory syndrome in children lacks a spe-cificdiagnostictermorcasedefinition,anditsharesseveralclini-cal features with Kawasaki disease (KD). We therefore exam-ineddiagnosesofKD(eTable3intheSupplement)observedinPEDSnetfromMarch1toMay15,2020,incomparisonwiththesameintervalsin2018and2019.Theat-riskdenominatorwasdefined as the mean number of patients seen between thesedatesin2018and2019.CasesweredefinedasallpatientswithaKDdiagnosiscodeduringthesameintervals.
Statistical Analysis
All statistical analyses were performed from September 8 to24, 2020, using R, version 3.6.1-4.0.2 (R Foundation for Sta-tisticalComputing).
27Wecomputedstandardizedratios(SRs)
of chronic disease risk by dividing the observed count of pa-tientswithdifferentPMCAbodysysteminvolvementwithanexpectedcountforthenumberofpatientspresentineachtestdenominatorgroup.Toascertaintheexpectedcount,wecom-putedchronicdiseaseproportionsforpatientswithavisitfromMarch1toSeptember8in2018or2019(combined)whoalsohadaviralillnessdiagnosisduringthoseintervals.Thesepro-portionswerethenmultipliedbythesamplesizeforalltestedpatients or patients with positive test results for each PMCAbody system category. The 95% CI was estimated using themethodofVandenbroucke.
28
Multivariable logistic regression was performed using
generalizedlinearmodels.Themodelincludedagecategory,race/ethnicity, PEDSnet health system, sex, testing location,andinsurancestatus.WealsocontrolledforpresenceofPMCAbodysystemdiagnosticcodes,inonemodelasacompositein-dicator and in another as independent variables so that onebody system was not overrepresented. One analysis com-prisedallrecurringpatientsandtheoutcomewaspresenceofa SARS-CoV-2 test. A second comprised only tested patientsand the outcome was a positive SARS-CoV-2 test result. Thethirdanalysisexaminedpatientswithpositivetestresultsandtheoutcomeofseveredisease.
Results
SARS-CoV-2 Testing
ThroughSeptember8,2020,atotalof135794patientsweretested for SARS-CoV-2 virus infection across PEDSnet (eFig-Research Original Investigation Assessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States
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ure1inthe Supplement).Atotalof13%oftestedpatientswere
younger than 1 year, 25% were 1 to 4 years, 27% were 5 to 11
years,25%were12to17years,and10%were18to24years.Atotalof53%weremale,themean(SD)agewas8.8(6.7)years,11% identified as Hispanic, 15% as Black, 3% as Asian or Pa-cific Islander, 3% as multiracial, and 59% as White, with 9%notcategorized(290per10000population[range,155-395per10000populationacrosshealthsystems]).Mostpatientstested(82%)wererecurringpatients( Table1).Overall,5374patients
(4%)hadpositivetestresultsforthevirus(12per10000popu-lation[range,7-16per10000population]).Thepositivityratefor recurring patients was 4%, while for nonrecurring pa-tients it was 6%. The proportions of new and recurring pa-tientswhounderwenttestingasinpatients,outpatients,orEDpatientsweresimilar.Thenumberoftestsperpatientrangedfrom1to28,with87%ofpatientsreceiving1test,9%receiv-ing 2 tests, 2% receiving 3 tests, and 2% receiving 4 or moretests.Thenumberoftestsperformedweeklyincreasedsharplyfrom 80 during the first week of March to 11519 during thethirdweekofJuly(eFigure2inthe Supplement );systemswith
higheroveralltestingvolumereachedtheirpeakrateseveralweeks before those with lower volume. This increase wasassociated with adoption of preemptive screening of inpa-tientsandpatientsscheduledtoundergoaerosol-generatingprocedures,suchasgeneralanesthesia.
Therewassubstantialvariationintheratesoftestingand
positivityacrossPEDSnet(Table1).Amongrecentpatients,thetestingratevariedfrom161to555per10000population(mean,338),or3%ofthepatientpopulationtested.Theoverallrateofpositivetestresultsrangedfrom1%to6%(eFigure3intheSupplement). The cumulative rate of SARS-CoV-2 infectionamong recent patients ranged from 6 to 17 per 10000 popu-lation, with an overall rate of 13 per 10000; the rate was 12per 10000 when the population was restricted to recurringpatientsonly.Characteristics of Patients Tested for SARS-CoV-2
Ahigherproportionofpatientswithnegativetestresultswereyoung children, had commercial insurance, and underwenttesting as inpatients. In contrast, patients with positive re-sults were more likely to be Black, Hispanic, or Asian; un-dergotestingintheED;andhavebeeninsuredbyapublicin-suranceprogramsuchasMedicaidatsomepoint( Table2).Of
the5374patientswithpositivetestresults,359(7%)metourcriteriaforsevereillness,thatis,wereadmittedwithrespira-tory, cardiovascular, or COVID-19–specific diagnosis codes(the most common case). These patients had higher inten-sivecareunituse(99[28%])andslightlyincreasedlengthofstay; 33 patients (9%) required ventilatory support. Overall,8patientswithpositivetestresultsdied(casefatalityrateof0.2%), 6 of whom had complex preexisting comorbidities;1 patient was inevaluable for chronic illness owing to lack offollow-uppriorto2020.
Association of Chronic Conditions
With SARS-CoV-2 Infection
Figure 1 shows associations between preexisting conditions,
combinedintobodysystemsusingthePMCAtaxonomy,and
testing for or proven infection with SARS-CoV-2. We reportthese as SRs of the number of patients in each categoryobservedinourcurrentdatatothatexpectedbasedon2018-2019 data. Except for malignant neoplasms, tested patientswere less likely to have all types of chronic conditions.However, several g roups were associated with increased
positive test results: malignant disorders (SR, 1.54 [95% CI,1.19-1.93]), cardiac disorders (SR, 1.18 [95% CI, 1.05-1.32]),endocrinologic disorders (SR, 1.52 [95% CI, 1.31-1.75]), gas-trointestinal disorders (SR, 2.00 [95% CI, 1.04-1.38]), geneticdisorders (SR, 1.19 [95% CI, 1.00-1.40]), hematologic disor-ders(SR,1.26[95%CI,1.06-1.47]),musculoskeletaldisorders(SR, 1.18 [95% CI, 1.07-1.30]), mental health disorders (SR,Table 1. SARS-CoV-2 Testing Patterns by Health System
Characteristic OverallHealth systema
ABCbDE F G H
Recent patients, No.c2 425 942 225 762 537 652 198 332 331 408 351 973 311 441 197 848 271 526
Patients tested, No. (%)
Recurringd111 785 (82) 9872 (93) 25 513 (93) 8657 (61) 22 920 (82) 10 594 (86) 15 684 (82) 11 929 (71) 6616 (95)
Nonrecurring 24 009 (18) 798 (7) 1961 (7) 5555 (39) 5043 (18) 1783 (14) 3539 (18) 4982 (29) 348 (5)
Test result, No. (%)
Positive 5374 (4) 425 (4) 1152 (4) 952 (7) 1046 (4) 751 (6) 503 (3) 250 (1) 295 (4)
Negative 130 420 (96) 10 245 (96) 26 322 (96) 13 260 (93) 26 917 (96) 11 626 (94) 18 720 (97) 16 661 (99) 6669 (96)
No. tested per 10 000
recent patients338 314 375 239 555 235 341 426 161
No. of cases ofSARS-CoV-2 infectionper 10 000 recentpatients13 13 16 11 17 15 10 6 8
Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
aThe Delaware and Florida sites in the Nemours Children’s Health System are
represented separately.
bPatients 18 years or older were removed owing to the presence in this healthsystem’s data of test information from adults seen at affiliated institutions.cPatients younger than 25 years with at least 1 physician visit with a recordeddiagnosis from July 2018 to December 2019.
dPatients with at least 2 in-person visits in the 3 years prior to testing,or to March 1, 2020, if not tested.Assessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States Original Investigation Research
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1.20 [95% CI, 1.10-1.30]), and metabolic disorders (SR,
1.42 [95% CI, 1.24-1.61]). Respiratory conditions were notassociated with increased positive test results (SR, 0.78[95% CI, 0.73-0.84]), nor was asthma specifically, whichhad a significant negative association (SR, 0.86 [95% CI,0.80-0.91]).
Consistentwiththeendocrinegroup,diagnosisoftype2
diabeteswasassociatedwithahigherlikelihoodofundergo-ing testing (SR, 2.67 [95% CI, 2.46-2.90]) and risk of positivetest results (4.10 [95% CI, 2.87-5.55]). We found the same tobetruefordiagnosisoftype1diabetes:SRof2.20(95%CI,2.05-2.35)fortestingandSRof3.67(95%CI,2.76-4.71)forpositivetestresults.
We also examined several drug categories in the 3 years
prior to testing. Children with use of bronchodilators or sys-temic corticosteroids had evidence of decreased testing andTable 2. Characteristics of Patients Tested for SARS-CoV-2 Infection
CharacteristicPatients, No. (%)
SARS-CoV-2–negative test
result (n = 130 420)SARS-CoV-2–positive test result
Asymptomatic or mild illness
(n = 5015)Severe illnessa
(n = 359)
Age, y
<1 17 431 (13) 494 (10) 72 (20)
1-4 32 619 (25) 808 (16) 40 (11)
5-11 35 617 (27) 1029 (21) 72 (20)
12-17 32 362 (25) 1521 (30) 117 (33)
18-24 12 391 (10) 1163 (23) 58 (16)
Sex
Female 61 637 (47) 2527 (50) 172 (48)
Male 68 701 (53) 2485 (50) 187 (52)
Other or unknown 82 (0.06) 3 (0.06) 0
Race/ethnicity
Hispanic 14 156 (11) 918 (18) 108 (30)
Asian or Pacific Islander 4471 (3) 151 (3) 9 (3)
Black or African American 18 646 (14) 1424 (28) 119 (33)
White 77 540 (60) 1988 (40) 97 (27)
Multiple 3883 (3) 126 (3) 5 (1)
Other or unknown 11 724 (9) 408 (8) 21 (6)
Payer
Commercial 45 219 (35) 1067 (21) 58 (16)
Public 46 363 (36) 2016 (40) 236 (66)
Other or unknown 38 838 (30) 1932 (39) 65 (18)
Testing locationb
Outpatient 72 102 (55) 2793 (56) 22 (6)
Emergency department 18 328 (14) 894 (18) 113 (32)
Inpatient 16 750 (13) 102 (2) 213 (59)
Other or unknown 23 240 (18) 1226 (24) 11 (3)
Visit within7do ftesting
Admission 20 967 (16) 130 (3) 307 (86)
Outpatient 109 453 (84) 4885 (97) 52 (15)
Among hospitalized patients
Length of stay, median (IQR) 2 (1-5) 2 (1-4) 3 (2-7.5)
Admitted to ICU 4843 (4) 22 (0.4) 99 (28)
Mechanical ventilation 907 (1.0) 4 (0.08) 33 (9)
Mortality 281 (0.2) 1 (0.02) 7 (2)
Obese
Yes 23 553 (18) 944 (19) 132 (37)
No 106 867 (82) 4071 (81) 227 (63)
Chronic condition
None 72 972 (56) 3132 (63) 172 (48)
1 Body system 25 222 (19) 1040 (21) 52 (15)
≥2 Body systems 32 226 (25) 843 (17) 135 (38)Abbreviations: COVID-19, coronavirus
disease 2019; ICU, intensive care unit;IQR, interquartile range;SARS-CoV-2, severe acute respiratorysyndrome coronavirus 2.
aSevere COVID-19 required a positiveSARS-CoV-2 test result,hospitalization starting no earlierthan 7 days before testing, and aninpatient diagnosis of pneumonia,sepsis, or COVID-19. All patientswith positive test results who didnot meet this definition wereclassified as having asymptomaticor mild illness.
bPercentages may not sum to 100%,as a single patient may have testsperformed in more than 1 location,and the location for some tests isnot known (eg, referencelaboratories and community testingsites).Research Original Investigation Assessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States
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testpositivity. However, childrentakingimmunomodulators
hadanincreasedlikelihoodoftesting(SR,1.15[95%CI,1.08-
1.23]) and of positive test results (SR, 2.37 [95% CI, 1.89-2.90]).
Demographic Correlates
To examine demographic factors that may be associatedwith outcomes of testing, we performed multivariableregression including chronic medical conditions, health sys-tem, and location of testing (outpatient, ED, or inpatient) aswell as demographic variables. Although Black, Hispanic,and Asian patients were significantly less likely to undergotesting (Black: odds ratio [OR], 0.70 [95% CI, 0.68-0.72];Hispanic: OR, 0.65 [95% CI, 0.63-0.67]; Asian: OR, 0.60[95% CI, 0.57-0.63]), these groups had a markedly increasedchance of a positive test result (Black: OR, 2.66 [95% CI,2.43-2.90];Hispanic:OR,3.75[95%CI,3.39-4.15];Asian:OR,2.04 [95% CI, 1.69-2.48]) (Table 3). Similarly, patients with ahistory of public insurance had a slightly lower likelihood ofundergoing testing compared with those with only commer-cial coverage (OR, 0.95 [95% CI, 0.93-0.97]), but the likeli-Figure 1. Standardized Ratios for Chronic Conditions
Among Pediatric Patients With Severe Coronavirus Disease 2019 Illness
0 1.5 2.0 1.0
Standardized ratio (95% CI)0.5Source
KidneyStandardized ratio
(95% CI)
Pulmonary or respiratoryPositive 1.15 (0.96-1.36)
Tested 0.71 (0.68-0.74)
Positive 0.78 (0.73-0.84)
Tested 0.27 (0.26-0.27)
Otologic
OphthalmologicPositive 0.82 (0.71-0.94)
Tested 0.41 (0.39-0.43)
Positive 1.00 (0.87-1.14)
Tested 0.53 (0.51-0.55)
Neurologic
MusculoskeletalPositive 1.00 (0.91-1.09)
Tested 0.48 (0.46-0.49)
Positive 1.18 (1.07-1.30)
Tested 0.49 (0.48-0.51)
Metabolic
Mental healthPositive 1.42 (1.24-1.61)
Tested 0.69 (0.66-0.71)
Positive 1.20 (1.10-1.30)
Tested 0.40 (0.39-0.41)
Malignant neoplasm
ImmunologicPositive 1.54 (1.19-1.93)
Tested 1.34 (1.26-1.42)
Positive 1.20 (0.97-1.46)
Tested 0.71 (0.67-0.75)
Hematologic
GenitourinaryPositive 1.26 (1.06-1.47)
Tested 0.72 (0.69-0.75)
Positive 1.29 (0.98-1.63)
Tested 0.61 (0.56-0.65)
Genetic
GastrointestinalPositive 1.19 (1.00-1.40)
Tested 0.80 (0.77-0.84)
Positive 1.20 (1.04-1.38)
Tested 0.91 (0.87-0.94)
Endocrinologic
DermatologicPositive 1.52 (1.31-1.75)
Tested 0.63 (0.61-0.66)
Positive 0.82 (0.56-1.12)
Tested 0.76 (0.71-0.82)
Craniofacial
CardiacPositive 1.01 (0.75-1.30)
Tested 0.63 (0.59-0.68)
Positive 1.18 (1.05-1.32)
Tested 0.62 (0.60-0.64) Less
likelyMore likely
Ratios were the quotient of observed number of patients with at least 1
condition in body system category and expected number. Expected values wereobtained by computing for each chronic condition category the proportion ofpatients seen from March 1 to May 15 in 2018 and 2019 and having an inclusiondiagnosis, and then multiplying these proportions by the total number ofpatients in the 2020 cohort (testing outcome) or undergoing testing (positiveresult outcome). A vertical line is placed at 1.0 for reference.Table 3. Logistic Regression of SARS-CoV-2 Test Use and Positivity
for Recurring Patients
CharacteristicaAdjusted odds ratio (95% CI)
Test performedb
(n = 218 537)Positive test result
(n = 102 919)
Age, y
<1 1.54 (1.49-1.59) 1.17 (1.03-1.33)
1-4 1 [Reference] 1 [Reference]
5-11 1.08 (1.05-1.11) 1.25 (1.13-1.38)
12-17 2.20 (2.13-2.26) 1.92 (1.73-2.12)
18-24 3.40 (3.24-3.57) 3.51 (3.11-3.97)
Sex
Male 1.13(1.11-1.16) 0.97 (0.91-1.04)
Female 1 [Reference] 1 [Reference]
Race/ethnicity
Hispanic 0.65 (0.63-0.67) 3.75 (3.39-4.15)
Asian or PacificIslander0.60 (0.57-0.63) 2.04 (1.69-2.48)
Black or AfricanAmerican0.70 (0.68-0.72) 2.66 (2.43-2.90)
White 1 [Reference] 1 [Reference]
Payer
Commercial 1 [Reference] 1 [Reference]
Public 0.95 (0.93-0.97) 1.43 (1.31-1.57)
Testing location Not applicable
Outpatient Not applicable 2.13 (1.86-2.44)
EmergencydepartmentNot applicable 3.16 (2.72-3.67)
Inpatient Not applicable 1 [Reference]
Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
aRegression models also adjusted for health system and chronic condition body
systems as fixed effects. They also included an “other” category forobservations with missing data for race/ethnicity, payer, and testing location.The 95% CIs were generated using the profile likelihood method forgeneralized linear models.
bThese analyses excluded data from 1 PEDSnet health system becauseinformation about recent patients was not available.Assessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States Original Investigation Research
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hood of a positive test result was modestly increSased (OR,
1.43 [95% CI, 1.31-1.57]). Testing performed in the outpatient(OR, 2.13 [1.86-2.44]) or ED setting (OR, 3.16 [95% CI, 2.72-3.67]) was more likely to yield a positive result comparedwith inpatient settings, as was testing for adolescents andyoung adults (aged 12-17 years: OR, 1.92 [95% CI, 1.73-2.12];and age 18-24 years: OR, 3.51 [95% CI, 3.11-3.97]). Groupingall chronic conditions into a single indicator variable yieldeda slightly decreased likelihood of positive test results. Sig-nificant differences were again observed in testing patternsacross health systems.
When investigating severe COVID-19, we first used a
single aggregate variable for any progressive condition, withsevere illness as the outcome. In this model, Black race/ethnicity (OR, 1.44 [95% CI, 1.02-2.04]), younger than 1 yearof age (OR, 2.96 [95% CI, 1.85-4.73]), 12 to 17 years of age(OR, 1.85 [95% CI, 1.22-2.81]), 18 to 24 years of age (OR, 1.63[95% CI, 1.02-2.61]), history of public insurance (OR, 1.91[95% CI, 1.27-2.87]), and presence of progressive condition(OR, 5.99 [95% CI, 4.51-7.96]) were significantly associatedwith severe illness among patients with SARS-CoV-2 infec-tion. In an alternate model using individual body systems,endocrinologic (OR, 2.17 [95% CI, 1.17-4.01]), metabolic (OR,2.34 [95% CI, 1.27-4.33]), and malignant involvement (OR,3.38 [95% CI, 1.32-8.63]) were associated with increased riskof severe infection.
Kawasaki Disease
WhencomparedwithcasecountsofKDfromMarch1toMay15in2018or2019,wedetecteda40%decreasein2020casecountsacrossallhealthsystems(259vs430in2019and433in2018).Thesecasecountstranslatetoadecreaseinpopula-tion rates (Figure 2), where the denominator is the mean ofpatientsseeninthese2018and2019intervals.
Withinthe2020viralillnesscohort,107patientswithKD
(41%)underwentSARS-CoV-2testing,and8ofthosepatients(8%) had positive test results. Six patients in the severe ill-nesscohortreceivedadiagnosisofKD.Discussion
InresponsetotheSARS-CoV-2pandemic,wehavemobilizedPEDSnet to rapidly evaluate the pediatric impact of SARS-CoV-2infectionacrosstheUnitedStates.Thisworkreflectsthecore principles of learning health systems, directly connect-ing health care delivery to learning about new challenges tochildhealth.
16,29PEDSnetisabletorapidlyestablishlearning
at large scale, to test hypotheses developed in smaller caseseries,andtodetectemergingpatternsofdiseasebiologyandtherapeuticeffectacrosslargepopulationsofchildren,whetherasacuteorlateeffectsofthevirus.
Wereporthereamulticenterstudyof135794pediatricpa-
tients tested for SARS-CoV-2 through September 8, 2020, inwhich 4% of patients were infected. Overall testing rates are338of10000recentpatients,andtheoverallinfectionrateis13 of 10000. Among the 5374 patients with positive test re-sults,thediseaseburdenwaslow,with7%ofpatientsmeet-ingarelativelybroaddefinitionofsevereillness.Thecasefa-talityratewas0.2%.
Amongtestedpatients,riskfactorsforinfectionincluded
increasingage,publicpayer,andHispanic,Black,orAsianrace/ethnicity. The rate of testing for patients from these racial/ethnicgroupswasbelowthatforWhitepatients.Furtherworkwill be needed to evaluate to what extent the higher rate ofpositivetestresultsreflectsdifferenttestingstrategiesacrosssubpopulations,differentsocialdeterminantsofrisk(eg,ex-posuretoairpollution,housingdensity,orlikelihoodoffam-ily continuing to work at in-person essential jobs), or differ-ences in disease biology associated with different rates ofsymptomaticpresentation.
Preexistingchronicdiseasealsoappearstobeassociated
with SARS-CoV-2 infection. This finding may result from agreater share of patients with chronic illness seeking testingwhen symptomatic (ie, higher prior probability of a positivetestresult)orbecausecertainchronicdiseasespredisposepe-diatricpatientstoinfection.Thefindingthatbothtypes1andFigure 2. Rates of Kawasaki Disease Diagnosis in the PEDSnet Population
20
15
10
5
0Kawasaki disease diagnoses/10 000 patients
Health system1 All 2 3 5 4 62018
2019
2020The mean number of patients seen
between March 1 and May 15 in 2018and 2019 was used to establish anat-risk denominator. Case countsbased on diagnoses assigned duringthis date interval were taken fromPEDSnet data for 2018 and 2019(for 1 PEDSnet health system,institution-supplied counts were usedthroughout) and reported separatelyby each health system (data forNemours Children’s Health Systemare reported here as a compositetotal) for 2020 to minimize datalatency. Vertical bars indicate95% CIs.Research Original Investigation Assessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States
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2 diabetes were associated with positive test results, as was
chronicuseofimmunomodulators,suggeststhatfurtherworkisneededtoidentifyspecificpatientswhomaybenefitfromadditionaltestingandriskreduction.
Our finding that the number of diagnosed cases of KD is
reducedin2020suggeststhatpatientspresentingwithMIS-ClikelydonotreceivediagnosesofKD,whichshouldnotbeusedasaproxyforthisnewentity.Becausespecificdiagnosticcod-ingforMIS-Cisnotyetavailable,computablephenotypesin-corporating other primary data, such as laboratory test val-ues,vitalsigns,andmedicaltherapy,willbeneededtoidentifypatientswiththiscondition.AlthoughwecannotexcludethepossibilitythatthereductioninKDdiagnosesistheresultofincompleteascertainmentowingtoloweroverallhealthcareuseduringthepandemic,itwouldbeunusualforasyndromeofthisseverity.ThedecreasednumberofcasesofKDalsoraisesthepossibilitythattrueKDislessprevalent,asmeasurestar-geting SARS-CoV-2 prevention also reduce the infection rateofotherpathogens.
30
Limitations
There are several limitations to this study, some inherent inthesecondaryuseofelectronichealthrecorddataandsomearising in the context of the rapidly changing pandemic re-sponse.Becauseouranalysesarebasedondatafromclinicalcareacrossalargepopulationofpatients,ourconclusionsmaybe influenced by evolving patterns in clinical decision-makingandhealthcareuse.Weusedviralgenomedetection,given its specificity for SAR S-CoV-2 infection. However, this
approachexcludespatientswithCOVID-19whenviraltestingwasnotreadilyavailableordifferentiallyavailableacrosssitesandexcludesthosewithasymptomaticormildcasesnotreach-ingcurrentthresholdsfortesting.Weexpectthislimitationwilldecreaseovertimeastestingbecomesmorewidelyavailable.Inaddition,thepopulationtestedmayreflectshiftingofchil-drenwithmoreacuteillnesstopediatrictertiarycarecentersofthetyperepresentedinPEDSnet,whichmayinflatetheob-servedinfectionrate.Paradoxically,increasingavailabilityoftestingcreatesasecondlimitation:becausehealthsystemsarecurrentlytargetingtestingtohigh-riskprocesses,suchasin-patientandsurgicalcare,evenwhenpatientsmaybeasymp-tomatic,thereisapotentialbiasinascertainmentofinfectionstatus,andtheassociationswedescribemayreflectpracticepatternratherthandiseasebiology.Wehaveattemptedtoad-dressthischallengebyexaminingassociationwithundergo-ing testing as well as positive test results, but more effectiveattributionwillrequirebroaderexaminationofavailabledata,suchascharacterizationoftreatmentpatternsorothertestre-sultsmoreindicativeofCOVID-19thanunderlyingillness.
In addition, limitations in the ability of standard termi-
nologies, such as SNOMED-CT and ICD-10-CM for diagnoses
and RxNorm for medications, to designate COVID-19–specificoutcomescomplicateidentificationofemergingphe-notypessuchasMIS-C.Moreover,significantdiscordanceex-istsbetweendiagnosiscodeuseandactualillnessforcomplexconditions, such as KD,
31kidney disease,32and leukemia.33
The breadth of primary data available in networks such asPEDSnet offers opportunities to develop accurate comput-ablephenotypesbyintegratingmultiplefactors,butthiswillrequiresustainedeffort.Finally,therecentonsetofthepan-demic limits our current understanding of rare or longer-termoutcomesofcoronaviralinfection.
Conclusions
Effective response to SARS-CoV-2 will require rapid but ro-bust development of new clinical and public health prac-tices, based on a better understanding of viral and host biol-ogy. This knowledge will be critical not only in caring forseverelyillpatients,butalsoinconstructingsustainablewaysto minimize the disease burden caused by SARS-CoV-2. Fur-therworkisneededinbothtraditionalmedicalresearchpara-digms and in rapid and highly collaborative science to pro-videbettercareforpediatricpatientsacrossthespectrumofhealth.
ARTICLE INFORMATION
Accepted for Publication: September 30, 2020.
Published Online: November 23, 2020.
doi:10.1001/jamapediatrics.2020.5052
Author Affiliations: Applied Clinical Research
Center, Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania (Bailey, Razzaghi,
Burrows, Bruno, Forrest); Department of
Biomedical and Health Informatics, Children’s
Hospital of Philadelphia, Philadelphia, Pennsylvania
(Bailey, Razzaghi, Camacho, Forrest); Department
of Pediatrics, Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania (Bailey
, Razzaghi,
Burrows, Forrest); Biomedical Research Informatics
Center, Nemours Biomedical Research, Alfred I.
duPont Hospital for Children, Wilmington, Delaware
(Bunnell, Eckrich); Seattle Children’s Research
Institute, University of Washington, Department of
Pediatrics, Seattle (Christakis, Ranade); Editor,
JAMA Pediatrics (Christakis); Research IT R&D,
Abigail Wexner Research Institute, Nationwide
Children’s Hospital, Columbus, Ohio (Kitzmiller);Department of Research Information Solutions and
Innovation, Nationwide Children’s Hospital,Columbus, Ohio (Lin); Institute for Informatics,Washington University School of Medicine in StLouis, St Louis, Missouri (Magnusen); Departmentof Pediatrics, St Louis Children’s Hospital, St Louis,Missouri (Newland); Division of PulmonaryMedicine, Cincinnati Children’s Hospital MedicalCenter, Cincinnati, Ohio (Pajor); Division ofBiomedical Informatics, Cincinnati Children’sHospital Medical Center, Cincinnati, Ohio (Pajor,Zahner); Department of Pediatrics, University ofCincinnati College of Medicine, Cincinnati, Ohio(Pajor); Department of Pediatrics (InfectiousDiseases, Hospital Medicine and Epidemiology),University of Colorado School of Medicine andChildren’s Hospital Colorado, Aurora (Rao);Research Informatics–Analytics Resource Center,Children’s Hospital Colorado, Aurora (Sofela).
Author Contributions: Dr Bailey had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of thedata analysis. Dr Bailey and Ms Razzaghicontributed equally to the work reported here.Concept and design: Bailey, Razzaghi, Christakis,
Rao, Sofela, Forrest.Acquisition, analysis, or interpretation of data:All authors.Drafting of the manuscript: Bailey, Razzaghi,
Camacho, Rao, Sofela, Bruno, Forrest.Critical revision of the manuscript for importantintellectual content: Bailey, Razzaghi, Burrows,
Bunnell, Christakis, Eckrich, Kitzmiller, Lin,Magnusen, Newland, Pajor, Ranade, Rao, Sofela,Zahner, Bruno.Statistical analysis: Bailey, Razzaghi, Burrows,
Bunnell, Forrest.Obtained funding: Forrest.
Administrative, technical, or material support:Bailey, Burrows, Bunnell, Camacho, Christakis,Eckrich, Kitzmiller, Lin, Magnusen, Pajor, Ranade,Rao, Sofela, Zahner, Bruno.Supervision: Bailey, Razzaghi, Forrest.
Conflict of Interest Disclosures: Drs Bailey,
Bunnell, Magnusen, and Pajor and Mss RazzaghiAssessment of 135 794 Pediatric Patients Tested for SARS-CoV-2 Across the United States Original Investigation Research
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and Zahner reported receiving grants from the
Patient-Centered Outcomes Research Institute(PCORI) during the conduct of the study.Dr Magnusen reported receiving grants fromPeople Centered Research Foundation during theconduct of the study. Ms Ranade reported receivinggrants from PEDSnet during the conduct of thestudy. No other disclosures were reported.
Funding/Support: This work was funded by PCORI
(RI-CRN-2020-007).Role of the Funder/Sponsor: Neither PCORI nor its
representatives participated directly in any of the
design and conduct of the study; collection,management, analysis, and interpretation of thedata; preparation, review, or approval of themanuscript; or decision to submit the manuscriptfor publication.
Disclaimer: Dr Christakis is editor of JAMA
Pediatrics; he was not involved in the editorial
review and decision for this manuscript.
Additional Contributions: The authors would like
to thank the following people from the PEDSnet
Data Coordinating Center at the Children’s Hospitalof Philadelphia: Susan Hague, MS, and ShwetaChavan, MSEE, for managing the data operationsand ensuring the availability of the data used foranalyses; and Kimberley Dickinson, BS, and LevonUtidjian, MD, for their contributions in reviewingdata quality for analyses. They were notcompensated for their contributions.
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