COVID-19 Disease Severity Risk Factorsfor Pediatric Patients in ItalyStefania Bellino, PhD,a,* Ornella Punzo, MD, PhD,a,* Maria Cristina Rota, MD,a Martina Del Manso, DStat,a

Alberto Mateo Urdiales, MD,a Xanthi Andrianou, PhD,a Massimo Fabiani, DStat,a Stefano Boros,a Fenicia Vescio, MD,Flavia Riccardo, MD,a Antonino Bella, DStat,a Antonietta Filia, MD, PhD,a Giovanni Rezza, MD,b Alberto Villani, MD, PhD,c

Patrizio Pezzotti, DStat,a COVID-19 WORKING GROUP

abstractOBJECTIVES: To describe the epidemiological and clinical characteristics of coronavirus disease(COVID-19) pediatric patients aged ,18 years in Italy.

METHODS: Data from the national case-based surveillance system of confirmed COVID-19infections until May 8, 2020, were analyzed. Demographic and clinical characteristics ofsubjects were summarized by age groups (0–1, 2–6, 7–12, 13–18 years), and risk factors fordisease severity were evaluated by using a multilevel (clustered by region) multivariablelogistic regression model. Furthermore, a comparison among children, adults, and elderly wasperformed.

RESULTS: Pediatric patients (3836) accounted for 1.8% of total infections (216 305); the medianage was 11 years, 51.4% were male, 13.3% were hospitalized, and 5.4% presented underlyingmedical conditions. The disease was mild in 32.4% of cases and severe in 4.3%, particularly inchildren #6 years old (10.8%); among 511 hospitalized patients, 3.5% were admitted in ICU,and 4 deaths occurred. Lower risk of disease severity was associated with increasing age andcalendar time, whereas a higher risk was associated with preexisting underlying medicalconditions (odds ratio = 2.80, 95% confidence interval = 1.74–4.48). Hospitalization rate,admission in ICU, disease severity, and days from symptoms onset to recovery significantlyincreased with age among children, adults and elderly.

CONCLUSIONS:Data suggest that pediatric cases of COVID-19 are less severe than adults; however,age #1 year and the presence of underlying conditions represent severity risk factors. Abetter understanding of the infection in children may give important insights into diseasepathogenesis, health care practices, and public health policies.

WHAT’S KNOWN ON THIS SUBJECT: Althoughcoronavirus disease is less frequent and often lesssevere in children compared with adults, limited dataexist on risk factors for disease severity and death inpediatric patients.

WHAT THIS STUDY ADDS: In the current study, wedescribe pediatric cases (persons aged ,18 years) ofsevere acute respiratory syndrome coronavirus 2infection in Italy and compare them with adult andelderly patients. Underlying medical conditions andyounger age represent risk factors for diseaseseverity among children and adolescents.

To cite: Bellino S, Punzo O, Rota MC, et al. COVID-19Disease Severity Risk Factors for Pediatric Patients inItaly. Pediatrics. 2020;146(4):e2020009399

aDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy; bGeneral Directorate for Prevention,Ministry of Health, Rome, Italy; and cGeneral Pediatrics and Infectious Diseases Unit, Pediatric Hospital BambinoGesù, Rome, Italy *Contributed equally as co-first authors

Dr Bellino performed the statistical analyses and drafted the manuscript; Dr Punzo contributed tocollect the clinical data and drafted the manuscript; Drs Rota, Filia, Rezza, and Prof Villani criticallyreviewed the manuscript; Drs Del Manso, Mateo Urdiales, Andrianou, Fabiani, Vescio, and Mr Boroscontributed to collect the data and conducted the final database; Dr Riccardo contributed to thecoordination of the coronavirus disease national surveillance; Dr Bella coordinated and supervisedthe surveillance data collection; Dr Pezzotti is the head of the Italian coronavirus diseasesurveillance system and revised the manuscript; and all authors approved the final manuscript assubmitted and agree to be accountable for all aspects of the work.

DOI: https://doi.org/10.1542/peds.2020-009399

Accepted for publication Jul 9, 2020

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The infection caused by the newsevere acute respiratory syndromecoronavirus 2 (SARS-CoV-2),associated to coronavirus disease(COVID-19), characterized by severepneumonia in a variable proportionof cases, was first reported in the cityof Wuhan,1–3 China, in December2019 and then spread acrosscontinents; first cases were initiallydiagnosed in Italy in late January inpeople coming from China.4

After the detection of the first locallyacquired case of SARS-CoV-2 infectionin the Lombardia region (NorthernItaly) on February 20,4 the number ofcases and deaths during thesubsequent weeks increased rapidly.5

Despite the high number of diagnosedsubjects, children are still a smallproportion of the cases in Italy.6 Thisis likely due to several factors;children are expected to experiencea milder disease,7 and testingstrategies privileged franklysymptomatic cases,8,9 especially inthe intensely hit northern regions inItaly.

The Chinese Center for DiseaseControl and Prevention reports that,of the 72 314 cases reported as ofFebruary 11, 2020, in China, only 2%were in individuals of ,19 years ofage.7 Children appear to be lesscommonly affected by SARS-CoV-2infection than adults, and to be morecommonly asymptomatic;7 however,in some cases, they can developcomplications, particularly infants.10

To date, data on clinical features andrisk factors for disease severity anddeath in infants, children, andadolescents are still limited, as well asa comparison with adults fordifferences in clinical characteristics,disease progression, and outcome.

Our objective with the current studyis to describe the epidemiological andclinical characteristics of COVID-19 inindividuals ,18 years old in Italy andcompare them with adults and theelderly.

METHODS

Study Population

The study population includedchildren aged ,18 years withlaboratory-confirmed COVID-19,reported to the Italian integratedCOVID-19 surveillance system.

According to the Italian casedefinition,11–13 all patients presentingto the health care system withsymptoms compatible with COVID-19infection or with an epidemiologicallink (close contact with a confirmedCOVID-19 case in the 14 days beforeonset of symptoms, or having beena resident or a staff member, in the14 days before onset of symptoms, ina residential institution for vulnerablepeople where ongoing COVID-19transmission has been confirmed),hospitalized patients with severeacute respiratory infections, and high-risk health care workers should betested for SARS-CoV-2 virus.11–13 Thecase definition considers asa confirmed case any person withlaboratory confirmation of SARS-Cov-2 virus, irrespective of clinical signsand symptoms.11–13

Study Outcomes

The primary outcomes of the studywere to outline the epidemiologicaland clinical characteristics of COVID-19 pediatric patients in Italy,investigate the disease severity riskfactors, and compare children andadolescents with adults and theelderly.

The clinical state was definedaccording to the followingclassification: asymptomatic (noapparent signs or symptoms ofdisease); paucisymptomatic (drycough, general malaise, low-gradefever, tiredness); mild (uncomplicatedupper respiratory tract viral infection[eg, fever, cough, sore throat, malaise,headache, muscle pain] withoutshortness of breath, dyspnea, orabnormal chest imaging); severe (eg,pneumonia, hypoxia dyspnea,tachypnea requiring hospitalization);

and critical (eg, severe pneumonia,acute respiratory distress syndrome,septic shock, and/or multiple organdysfunction requiring hospitalizationin intensive care). However, in severalcases, the information about theseverity of the disease was missing orthe case was reported by the Regionsas “symptomatic.” Recovery wasdefined as resolution of clinicalsymptoms with 2 negative reversetranscription polymerase chainreaction (RT-PCR) results fromrespiratory specimens at 24-hourintervals.14

The Italian Integrated COVID-19Surveillance System

With the aim to monitor the epidemicin Italy and support the planning ofpublic health actions, a case-basedsurveillance system was establishedon February 27, 2020. The systemcontains case-based data on alllaboratory-confirmed cases of COVID-19 as per the case definition by theEuropean Centre for DiseasePrevention and Control regularlyupdated.11–13 From the beginning ofthe outbreak until March, allnasopharyngeal swabs tested positiveby RT-PCR at regional level were sentfor confirmation to the NationalReference Laboratory at the IstitutoSuperiore di Sanità and retestedaccording to the World HealthOrganization and Centers for DiseaseControl and Prevention protocols.15,16

Because of the high concordance(99%) of results with the regionallaboratories, the policy was thenchanged, allowing selected referenceregional laboratories, withdemonstrated capacity, to directlyconfirm COVID-19 suspected cases,using a selected number of RT-PCR–based commercial diagnostictests for SARS-CoV-2.13

Data Sources

Data from the Italian case-basedsurveillance system of confirmedSARS-CoV-2 infections until May 8,2020, collected from all 21 regionsand autonomous provinces, were

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analyzed, considering patients aged,18 years who tested positive forSARS-CoV-2. The nationalsurveillance system is coordinated bythe Istituto Superiore di Sanità, anddata were collected by using a secureonline platform or received asindividual data sets (from 3 regions)to be included in a single database.Data collected on all laboratory-confirmed cases include informationon demographics, clinical severity,underlying medical conditions, dateof symptoms onset, date of diagnosis,date of hospitalization, clinicaloutcome, region of diagnosis, andprovince of residence. Information onunderlying conditions was collectedbased on anamnestic data, accordingto the following categories:cardiovascular, respiratory, oncologic,neurologic, liver, and renal diseases;metabolic disorders; diabetes;immunodeficiency; and obesity.Details on the 4 deaths that occurredin children were retrieved from themedical records.

The study was conducted as part ofpublic health and surveillanceactivities for the COVID-19emergency, which were entrusted toIstituto Superiore di Sanità.17 Becauseof the nature of aggregated data andthe ongoing public health response tocontrol the outbreak, as well as the

importance of sharing the researchfindings, full ethical approval was notjuridically required for surveillanceactivities. However, the IstitutoSuperiore di Sanità Research EthicsCommittee was informed.

Statistical Analysis

The x2 test for categorical variablesand Kruskal–Wallis test forcontinuous variables were used tocompare cases among age groups fordemographic and clinicalcharacteristics.

The absolute number of pediatriccases was aggregated by regions andautonomous provinces as well as thecumulative incidence (per 100 000inhabitants), calculated by usingpopulation estimates aged ,18 yearsfor 2019 available from the ItalianNational Institute of Statistics; 4 areaswere detected on the basis of thequartiles of the national distributionof the pediatric population (low,medium, high, very high). In addition,on the basis of the severity of COVID-19 (considering the highest severitybetween baseline and follow-up), riskfactors for mild, severe, or criticaloutcome versus asymptomatic orpaucisymptomatic clinical state wereevaluated by using a multilevel(clustered by region) multivariablelogistic regression model, includingsex, age groups (0–1, 2–6, 7–12,

13–18 years), presence of pre-existing underlying medicalconditions, and calendar time:February 20 to March 23 (the firstmonth of the epidemic), March 24 toApril 15 (3 weeks after the peak ofthe epidemic), and April 16 to May 8(the last 3 weeks of observationduring the declining phase). Finally,a comparison for demographic andclinical characteristics was performedamong children (,18 years), adults(18–64 years), and elderly ($65years) by using the x2 test forcategorical variables andKruskal–Wallis test for continuousvariables.

Statistical analysis was conducted byusing the Stata software, version 16(Stata Corporation, CollegeStation, TX).

RESULTS

COVID-19 Epidemiology in Childrenand Adolescents

In Italy, 16% of the residents aremade up of infants, children, andadolescents aged ,18 years. As ofMay 8, 2020, this pediatric populationaccounted for 1.8% (3836 of216 305) of all COVID-19–reportedcases at the national level, witha variable percentage across theItalian regions. Considering all

FIGURE 1Epidemic curve by date of positive test result of COVID-19 cases aged ,18 years (A) and aged 18 to 64 or $65 years (B), Italy, February 20 to May 8, 2020.

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patients aged ,18 years with anavailable date of diagnosis (3720,97%), a continuous daily increase ofthe diagnosed cases from February23 (the first reported pediatric case)until the peak of the outbreak (March24–26) was found (2 weeks after thenational lockdown), whereas sincethen, a gradual and steady decreasewas observed until the first week ofMay (Fig 1A). An interregionalvariation for pediatric COVID-19patients was observed in Italy; thehighest absolute number of patientswas reported in the Northern regions(Lombardia, Emilia-Romagna, Veneto,and Piemonte), the most hit by theepidemic (Fig 2A), whereas majorincidence rates were detected inAutonomous Province of Trento(180.6 per 100 000), Valle d’Aosta(115.1 per 100 000 population),

Emilia-Romagna (75.5 per 100 000),Abruzzo (73.8 per 100 000), andAutonomous Province of Bolzano(62.5 per 100 000) (Fig 2B).

Demographic and ClinicalCharacteristics of Pediatric Patients

The epidemiological history mostfrequently reported wasa relationship with a familial cluster,followed by a contact witha confirmed case. Most cases ofCOVID-19 occurred in adolescentsaged 13 to 17 years (40.1%),followed by those in children 7 to 12(28.9%), 2 to 6 (17.2%), and 0 to 1(13.8%) years old; the median agewas 11 years, and 51.4% of themwere male (Table 1). The median timefrom symptoms onset to diagnosisincreased with age, from 3 daysamong infants to 6 days among

adolescents (P , .001) as well as themedian time from symptoms onset tohospitalization, from 1 day amonginfants to 4 days among adolescents(P = .001). Overall, the hospitalizationrate was 13.3%, and the highestpercentage of hospital admissionoccurred in infants aged #1 year(36.6%), followed by children aged 2to 6 years (12.8%), 13 to 17 years(8.9%), and 7 to 12 years (8.8%) (P,.001); the admission rate in ICU was3.5%, with the highest value amongchildren aged 2 to 6 years (9.5%) (P =.010). Preexisting underlying medicalconditions increased with age, from3.6% in infants #1 year old to 6.0%in adolescents 13 to 17 years old (P,.001), and were particularly high(9.8%) among hospitalized patients;the most common were respiratory,cardiovascular, and oncologic

FIGURE 2Absolute number (A) and incidence rates per 100 000 population (B) of COVID-19 cases aged ,18 years by Italian regions and autonomous provinces ofdiagnosis. IR, incidence rate.

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diseases. Among patients withavailable clinical state classification(2015, 52% of the total), youngerchildren, particularly infants, showedthe highest proportion of severeinfections (P , .001); specifically, theproportions of severe or critical statewere 10.8%, 6.5%, 2.4%, and 3.0%for age groups 0 to 1, 2 to 6, 7 to 12,and 13 to 17 years old, respectively(Table 1).

After adjusting for sex, age groups,underlying medical conditions, andcalendar time of diagnosis, a lowerrisk of disease severity (mild, severe,or critical as compared withasymptomatic or paucisymptomatic)was detected with increasing agecompared with infants #1 year old(2–6 years, odds ratio [OR] = 0.30,95% confidence interval [CI] =0.20–0.46; 7 to 12 years, OR = 0.22,95% CI = 0.15–0.33; 13 to 17 years,OR = 0.26, 95% CI = 0.18–0.37),whereas a higher risk was associatedwith the presence of $1 preexistingunderlying medical condition (OR =2.80, 95% CI = 1.74–4.48). Thesecond period after the peak of the

outbreak was associated with a lowerrisk of disease severity as comparedwith the first month (February 23 toMarch 23) of the epidemic (OR = 0.61,95% CI = 0.47–0.80, March 24 toApril 15; OR = 0.33, 95% CI0.23–0.46, April 16 to May 8);moreover, high interregional variationwas observed, and approximately halfof the disease severity variability wasattributable to the region effect(Table 2).

COVID-19–Related Deaths in Children

Four deaths were reported inchildren, and clinical details aredescribed below.

The first case was of a 5-year-old girlwho died in hospital with SARS-CoV-2pneumonia. The patient had a type-2mucolipidosis (an inherited metabolicdisease) associated with hypertrophiccardiomyopathy, with thickening ofthe mitral and aortic valves and sleepapnea syndrome. The patient wastreated with antibiotics andcorticosteroids, then oxygen wasadded, but when the generalconditions deteriorated, a palliative

care protocol was started. The secondcase was of an infant aged 2 monthswith Williams syndrome, a raremultisystemic genetic disease ofneurologic development,characterized by typical facialfeatures, heart disease (especiallysupravalvular aortic stenosis), andcognitive, developmental, andconnective tissue abnormalities (jointlaxity). The infant presented stenosisand hypoplasia of the pulmonaryarteries and supravalvular aorticstenosis. He was admitted for cardiacsurgery and underwent a complexsurgical procedure. Although hesurvived the procedure, he remainedon extracorporeal membraneoxygenation and could never beweaned from that in the followingdays and finally died 10 days after thesurgery. The third case was of aninfant aged 6 months with a rare andaggressive form of cancer (ie, anextrarenal malignant rhabdoidtumor) who underwent 10 cycles ofchemotherapy and developed feverassociated to neutropenia andpneumonia. The last case was of a 6-year-old girl who suffered from heart

TABLE 1 Demographic and Epidemiological Characteristics of Individuals ,18 Years of Age With COVID-19 in Italy, February 23 to May 8, 2020

Class of Age, y P

0–1 2–6 7–12 13–17

Total cases, n (%) 528 (13.8) 659 (17.2) 1109 (28.9) 1540 (40.1) —

Female 245 (46.4) 300 (45.5) 542 (48.9) 779 (50.6) .11Male 283 (53.6) 359 (54.5) 567 (51.1) 761 (49.4) —

Hospitalization, n (%) 193 (36.6) 84 (12.8) 97 (8.8) 137 (8.9) ,.001ICU 5 (2.6) 8 (9.5) 1 (1.0) 4 (2.9) .010

Underlying conditions, n (%) 19 (3.6) 31 (4.7) 64 (5.8) 92 (6.0) ,.001Respiratory disease 0 (0.0) 4 (12.9) 9 (14.1) 15 (16.3) .31Cardiovascular 2 (10.5) 3 (9.7) 5 (7.8) 7 (7.6) .96Oncologic 2 (10.5) 3 (9.7) 2 (3.1) 4 (4.4) .40Metabolic, diabetes 1 (5.3) 1 (3.2) 3 (4.7) 6 (6.5) .90Neurologic 1 (5.3) 0 (0.0) 3 (4.7) 2 (2.2) .53Immunodeficiency 1 (5.3) 3 (9.7) 2 (3.1) 0 (0.0) .04

Disease severity, n (%)Asymptomatic 43 (20.2) 141 (40.1) 267 (44.5) 334 (39.3) ,.001Paucisymptomatic 43 (20.2) 84 (23.9) 149 (24.8) 216 (25.4) —

Mild 104 (48.8) 104 (29.5) 170 (28.3) 274 (32.2) —

Severe 21 (9.9) 20 (5.7) 13 (2.2) 25 (2.9) —

Critical 2 (0.9) 3 (0.9) 1 (0.2) 1 (0.1) —

Recovery, n (%) 322 (61.0) 412 (62.5) 654 (59.0) 968 (62.9) .21Deaths, n (%) 2 (0.4) 2 (0.3) 0 (0.0) 0 (0.0) .03Days from symptoms to diagnosis, median (IQR) 3 (1–7) 4 (2–10) 5 (2–11) 6 (2–12) ,.001Days from symptoms to hospitalization, median (IQR) 1 (0–4) 2 (1–5) 2 (1–5) 4 (1–8) .001Days from symptoms to recovery, median (IQR) 28 (23–37) 27 (22–35) 29 (23–36) 32 (22–39) .06

The x2 test for categorical variables and Kruskal–Wallis test for continuous variables were used to compare the 4 age groups. IQR, interquartile range; —, not applicable.

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failure and underwent a mitralannuloplasty due to severe mitralinsufficiency and left ventriculardysfunction. This hospitalization wasassociated with a series ofcomplications, consisting ofsuperinfection and deterioration ofcardiac failure.

Based on medical records and fromthe treating physicians’ notes, all 4children died of a deterioration ofvery compromised conditions, and toa certain extent the impact of SARS-CoV-2 infection may have aggravatedthe situation but does not seem to bethe underlying cause of death.

Comparison Among Pediatric, Adult,and Elderly Populations

Evolution of the reported COVID-19cases in Italy followed a similar trendamong children (,18 years), adults(18–64 years), and elderly ($65years) from February to May (Fig 1 Aand B). More female individuals wereaffected by COVID-19, except forthose aged ,18 years (P , .001)(Table 3); men showed more severesymptoms compared with women(P , .001) among adults and elderly,whereas no sex difference was foundamong children. Hospitalization rate

significantly increased with age (P ,.001); indeed, 13.3% of children werehospitalized compared with adults(28.3%) and elderly (49.9%), andamong hospitalized patients, adults(13.0%) were the most admitted inICU (P , .001) as compared withchildren (3.5%) and elderly (10.2%)(Table 3). Disease severity alsosignificantly increased with age (P ,.001); 4.2% of children had severe orcritical symptoms, compared withadults (17.2%) and elderly (41.1%),whereas 63.4% of children wereasymptomatic or paucisymptomatic,compared with adults (44.0%) andelderly (27.3%). About half ofpatients recovered within 1 monthfrom the onset of the disease; therecovery rate was higher in children(38.6%) and adults (41.9%)compared with the elderly (20.2%)(P , .001). Moreover, a shorterperiod from symptoms onset tohospitalization and recovery wasfound among children compared witholder ages (P , .001). In general,pediatric patients with COVID-19 hada good prognosis, although 4 deathsoccurred, whereas the mortality ratewas 5.8% among adults withunderlying medical conditions and25.8% among the elderly.

DISCUSSION

This is the first large study offeringa comprehensive picture of thepediatric population diagnosed withSARS-CoV-2 infection in Italy. Afterthe first indigenous case of COVID-19diagnosed on February 20, thenumber of cases rapidly increasednationwide until the peak of theepidemic, which occurred ∼2 weeksafter the national lockdown declaredon March 11. A steady and gradualdecrease has been observed sinceMarch 26; however, data referred tothe last week of observation (May2–8) might be influenced by reportingdelay of the more recently diagnosedcases. Of note, the median delaybetween the date of symptoms onsetand the date of the positive test resultin the 3 study periods was 3, 5, and 9days, respectively.

As of May 8, 2020, just after the startof the lockdown easing in Italy,patients ,18 years old accounted for1.8% of all reported COVID-19 cases.This relatively low burden amongchildren has also been observed inother countries,18,19 but the agedistribution might reflect testingpolicies and case definitions, whichusually include the presence of

TABLE 2 Risk Factors for Disease Severity (Mild, Severe, or Critical Versus Asymptomatic, Paucisymptomatic) in Individuals ,18 Years of Age; MultilevelMultivariable Logistic Regression Model, Italy, February 23 to May 8, 2020

Risk factors Disease Severity

OR 95% CI P

SexMale Reference — —

Female 0.96 0.77–1.20 .73Class of age, y0–1 Reference — —

2–6 0.30 0.20–0.46 ,.0017–12 0.22 0.15–0.33 ,.00113–17 0.26 0.18–0.37 ,.001

Underlying conditionsNo Reference — —

Yes 2.80 1.74–4.48 ,.001Calendar timeFebruary 23 to March 23 Reference — —

March 24 to April 15 0.61 0.47–0.80 ,.001April 16 to May 8 0.33 0.23–0.46 ,.001

Regions (random effect)Variance among regions 4.18 2.04–8.59 ,.001ICC (%) 56.0 38.2–72.3 —

ICC, intraclass correlation (proportion of variation that is attributable to the effect of clustering [Italian regions]); —, not applicable.

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symptoms; moreover, it may bepossible that the small proportion ofinfected children reflects a lower riskof younger subjects developingdisease symptoms. Of note, a surveyconducted in the municipality of Vo’in Italy revealed a prevalence ofSARS-CoV-2 infection of 2.6% in thepopulation, and 43.2% of theconfirmed cases wereasymptomatic.20 At the national level,the disease cumulative incidence ratewas 40 per 100 000 and 419 per100 000 in subjects aged ,18 and$18 years, respectively. Thedistribution of pediatric cases variedthroughout the country, with most ofthem concentrated in northern Italy;however, differences in incidencerates may be due to different testingstrategies implemented at the locallevel (ie, children with a more seriousinfection are more likely to be tested)or to existing specific clusters.Furthermore, children were usuallydiagnosed with COVID-19 afterexposure to an infected adult withinthe family circle. Children of all ageswere found positive to COVID-19,suggesting that susceptibility is alwayspresent. Clinical manifestations wereless severe than in adults; however,among pediatric patients, youngerchildren were more vulnerable,particularly infants aged #1 year, who

were hospitalized in approximatelya third of cases; instead, children aged2 to 6 years were the most frequentlyadmitted in ICU.

Lower risk of disease severity wasdetected with increasing age, whereasa higher risk was associated with thepresence of pre-existing underlyingmedical conditions. Moreover, ourstudy highlighted that the secondperiod of the outbreak was associatedwith a lower risk of severe disease.Indeed, the percentage of pediatricpatients with severe or criticalsymptoms slightly decreased overtime, from 5.4% in the first month ofthe outbreak to 3.5% during the last3 weeks of the observation period, asdid the percentage of patients withmild symptoms, from 43.4% to28.9%. Nevertheless, this seems duemore to the effect of the phase of theepidemic (during the peak of theoutbreak, only subjects with clearsigns and symptoms of the diseasewere tested) and probably to a moreefficient health care provision due toa decreasing number of cases in thesecond phase rather than to a changein the pathogenicity of the SARS-CoV-2. The shifts of COVID-19 in terms ofclinical presentation and outcome asthe disease moved out from Chinainto Europe and the rest of the world

is still under debate; however, ourdata support the hypothesis that thedisease course and severity have notundergone major changes. Theevolution of the virus throughout thepandemic is not occurring faster thanexpected compared with otherviruses during an outbreak.21

Different clades are emerging asCOVID-19 spread worldwide, anda study in which researchersperformed genetic analyses of 86complete or near-complete genomesof SARS-CoV-2 from 12 countriesrevealed many mutations anddeletions on coding and noncodingregions.22 This provided evidence ofthe genetic diversity and evolution ofthis novel coronavirus, although itdoes not mean that the emerged newstrains are more pathogenic thanothers circulating right now.21

Our findings are in line with those inpublished studies in which authorsdescribe the epidemiology of COVID-19 among pediatric patients inChina19,23 and the United States,24 interms of percentage of children onthe overall population, clinicalseverity, hospitalization, andoutcome.

As reflected in our analysis, authorsof previous studies also showed thatchildren of all ages are susceptible to

TABLE 3 Demographic and Clinical Characteristics of Children, Adults, and Elderly With COVID-19 in Italy, February 20 to May 8, 2020

Children ,18 y Adults 18–64 y Elderly $65 y P

Median age (IQR) 11 (5–15) 49 (39–56) 81 (73–87) —

Total cases, n (%) 3836 (1.8) 111 431 (51.5) 100 977 (46.7) —

Female 1866 (48.6) 59 245 (53.3) 54 432 (54.0) —

Male 1970 (51.4) 51 957 (46.7) 46 438 (46.0) ,.001Hospitalization, n (%) 511 (13.3) 31 547 (28.3) 50 347 (49.9) ,.001ICU 18 (3.5) 4115 (13.0) 5127 (10.2) ,.001

Underlying conditions, n (%) 206 (5.4) 22 570 (20.2) 54 412 (53.9) ,.001Disease severity, n (%)Asymptomatic 785 (39.0) 7959 (20.0) 3539 (13.0) ,.001Paucisymptomatic 492 (24.4) 9523 (24.0) 3885 (14.3) —

Mild 652 (32.4) 15 422 (38.9) 8627 (31.7) —

Severe 79 (3.9) 5854 (14.8) 9519 (35.0) —

Critical 7 (0.3) 940 (2.4) 1661 (6.1) —

Recovery, n (%) 1480 (38.6) 46 665 (41.9) 20 346 (20.2) ,.001Deaths, n (%) 4 (0.1) 2428 (2.2) 26 011 (25.8) ,.001Days from symptoms to diagnosis (median, IQR) 5 (2–11) 6 (3–11) 6 (2–10) ,.001Days from symptoms to hospitalization (median, IQR) 2 (1–5) 7 (3–10) 5 (2–9) ,.001Days from symptoms to recovery (median, IQR) 29 (23–37) 32 (24–40) 35 (27–43) ,.001

x2 test for categorical variables and Kruskal–Wallis test for continuous variables were used to compare the 3 age groups. IQR, Interquartile range; —, not applicable.

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SARS-CoV-2 infection, but they seemto be less affected than the adultpopulation, besides presenting withmilder symptoms.23,25,26 Althougha minority of children with COVID-19require hospitalization, severe caseshave been reported.10,27 Moreover,although children are most commonlyinfected through familial clusters,they were less likely to becomepositive, when exposed, than adults.28

Concerning the disease severity,especially for the more severe cases,our data were comparable with a studyon 2135 children from China including728 laboratory-confirmed cases, inwhich researchers found that 5% weresevere (presenting hypoxemia, dyspnea,central cyanosis), and,1%were critical(with respiratory failure, acuterespiratory distress syndrome, shock).23

It is unclear why children showedmilder symptoms of COVID-19. Acytokine storm has been involved inthe pathogenesis of severe forms ofthe disease in adults29; therefore, onepossible explanation could bea weaker immune response to SARS-CoV-2 in children compared withadults. Other hypotheses take intoaccount a possible viral “competition”in the respiratory tract of youngchildren and the expression of theangiotensin-converting enzyme 2receptor. In the first scenario, viralinterference may lead to a lower viralload in children. As for theangiotensin-converting enzyme 2receptor, it acts as the receptor forSARS-CoV-2 and it may be expresseddifferently in the respiratory tract ofchildren compared with adults.30,31

A recent study showed that the viralload of symptomatic andasymptomatic patients were similar,and asymptomatic patients can stillinfect others.32 These “silent patients”may remain undiagnosed and be ableto spread the disease to largenumbers of people.33 However, theextent to which children can act assources of infection is still underdebate, also because of physicaldistancing and the closure of schools.

Of note, the European Centre forDisease Prevention and Control isclosely following the informationabout the emergence ofa postinflammatory syndrome inchildren in Europe, with a possibleconnection to COVID-19,34 and onMay 15, 2020, the World HealthOrganization gave a preliminary casedefinition because of the urgent needfor the collection of standardized datadescribing clinical presentations,severity, outcomes, andepidemiology.35

Unfortunately, the data reported inour database do not allow theidentification of children witha multisystem inflammatory disorder.

Before drawing any conclusion, somelimits of the study should bementioned. In particular, the datawere collected in a continuousconsolidation phase and, asforeseeable in an emergencysituation, some information wasincomplete. Moreover, differenttesting strategies may have beenapplied regionally because eachregion is responsible for planning andorganizing its health services;therefore, the number of swabs perresidents, as well as the ability todetect less serious cases in the periodafter the epidemic peak, varied in theItalian regions. Finally, we were unableto assess clinical data, such as chestradiography, pulmonary lesions, andhematologic and biochemicalparameters; therefore, additional studiesare required to understand clinical andlaboratory findings associated withpediatric cases of COVID-19.

CONCLUSIONS

Pediatric cases account for a smallpercentage of COVID-19 patients inItaly, and disease in children was oftenmilder than in adults. Severe diseasecases in children were associated withyounger age and underlying conditions.Infection control measures should beimplemented to prevent COVID-19nosocomial spread, with the need to

protect vulnerable individuals andchildren with serious underlyingconditions.

A widespread availability of testingmay allow us to better understandthe infection in children, givingimportant insights into diseasepathogenesis, health care practices,and public health policies.

ACKNOWLEDGMENTS

We thank all local health personnelinvolved in the COVID-19 outbreak.

The COVID-19 working group is asfollows: Paolo D’Ancona, AndreaSiddu, Roberta Urciuoli, StefaniaGiannitelli, Paola Stefanelli,Alessandra Ciervo, Corrado DiBenedetto, and Marco Tallon, (IstitutoSuperiore di Sanità); regionalrepresentatives: Manuela Di Giacomo(Abruzzo), Michele La Bianca(Basilicata), Anna Domenica Mignuoli(Calabria), Angelo D’Argenzio(Campania), Erika Massimiliani(Emilia-Romagna), Tolinda Gallo(Friuli Venezia Giulia), PaolaScognamiglio (Lazio), Camilla Sticchi(Liguria), Danilo Cereda (Lombardia),Daniel Fiacchini (Marche), FrancescoSforza (Molise), Maria Grazia Zuccaro(P.A. Bolzano), Pier Paolo Benetollo(P.A. Trento), Daniela Tiberti(Piemonte), Maria Chironna (Puglia),Maria Antonietta Palmas (Sardegna),Salvatore Scondotto (Sicilia), LuciaPecori (Toscana), Anna Tosti(Umbria), and Mauro Ruffier(Valle D’Aosta); and Filippo Da Re(Veneto).

ABBREVIATIONS

CI: confidence intervalCOVID-19: coronavirus diseaseOR: odds ratioRT-PCR: reverse transcription

polymerase chainreaction

SARS-CoV-2: severe acute respira-tory syndromecoronavirus 2

8 BELLINO et al by guest on May 15, 2021www.aappublications.org/newsDownloaded from

Address correspondence to Stefania Bellino, PhD, Department of Infectious Diseases, Istituto Superiore di Sanità, viale Regina Elena, 299, 00161 Rome, Italy.

E-mail: stefania.bellino@iss.it

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

Copyright © 2020 by the American Academy of Pediatrics

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

FUNDING: No external funding.

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

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DOI: 10.1542/peds.2020-009399 originally published online July 14, 2020; 2020;146;Pediatrics 

Patrizio Pezzotti and COVID-19 WORKING GROUPFlavia Riccardo, Antonino Bella, Antonietta Filia, Giovanni Rezza, Alberto Villani,

Mateo Urdiales, Xanthi Andrianou, Massimo Fabiani, Stefano Boros, Fenicia Vescio, Stefania Bellino, Ornella Punzo, Maria Cristina Rota, Martina Del Manso, Alberto

COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy

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DOI: 10.1542/peds.2020-009399 originally published online July 14, 2020; 2020;146;Pediatrics 

Patrizio Pezzotti and COVID-19 WORKING GROUPFlavia Riccardo, Antonino Bella, Antonietta Filia, Giovanni Rezza, Alberto Villani,

Mateo Urdiales, Xanthi Andrianou, Massimo Fabiani, Stefano Boros, Fenicia Vescio, Stefania Bellino, Ornella Punzo, Maria Cristina Rota, Martina Del Manso, Alberto

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