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www.analesdepediatria.org

SPANISH ASSOCIATION OF PAEDIATRICS

Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS) ^夽

Alberto García-Salido

, Jordi Antón

, José David Martínez-Pajares

, Gemma Giralt Garcia

, Borja Gómez Cortés

, Alfredo Tagarro

,

Grupo de trabajo de la Asociación Espa˜ nola de Pediatría para el Síndrome Inflamatorio Multisistémico Pediátrico vinculado a SARS-CoV-2

aSociedadEspa˜noladeCuidadosIntensivosPediátricos(SECIP)

bCuidadosIntensivosPediátricos,HospitalInfantilUniversitarioNi˜noJesús,Madrid,Spain

cSociedadEspa˜noladeReumatologíaPediátrica(SERPE)

dHospitalSantJoandeDéu,InstitutdeRecercaSantJoandeDéu(IRSJD),Barcelona,Spain

eSociedadEspa˜noladePediatríaHospitalaria(SEPHO)

fUnidaddePediatría,HospitaldeAntequera,ÁreaSanitariaNortedeMálaga,Málaga,Spain

gSociedadEspa˜noladeCardiologíaPediátricayCardiopatíasCongénitas(SECPCC)

hHospitalUniversitarioHospitalValld’Hebron,HospitalUniversitarioValld’Hebron,Barcelona,Spain

iSociedadEspa˜noladeUrgenciasdePediatría(SEUP)

jServiciodeUrgenciasdePediatría.HospitalUniversitarioCruces,Barakaldo

kSociedadEspa˜noladeInfectologíaPediátrica(SEIP)

lServiciodePediatría,HospitalUniversitarioInfantaSofía,UnidadPediátricadeInvestigaciónyEnsayosClínicos(UPIC),Instituto deInvestigaciónSanitariaHospital12deOctubre(IMAS12),Madrid,Spain

Received12August2020;accepted15September2020 Availableonline14January2021

KEYWORDS Multisystem inflammatory syndrome;

Paediatrics;

SARS-CoV-2

Abstract A newpaediatricmultisysteminflammatorysyndrome,linkedtoSARS-CoV-2(MIS- Paed),hasbeendescribed.Theclinicalpictureisvariableandisassociatedwithanactiveor recentinfectionduetoSARS-CoV-2.Areviewoftheexistingliteraturebyamultidisciplinary groupofpaediatricspecialistsispresentedinthisdocument.Later,theymakerecommendations onthestabilisation,diagnosis,andtreatmentofthissyndrome.

©2020Asociaci´onEspa˜noladePediatr´ıa.PublishedbyElsevierEspa˜na,S.L.U.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/

4.0/).

夽 Pleasecitethisarticleas:García-SalidoA,AntónJ,DavidMartínez-PajaresJ,GarciaGG,CortésBG,TagarroA.Documentoespa˜nol deconsensosobrediagnóstico,estabilizaciónytratamientodelsíndromeinflamatoriomultisistémicopediátricovinculadoaSARS-CoV-2 (SIM-PedS).Estudiobeenis.AnPediatr(Barc).2021;94:118.

∗Correspondingauthor.

E-mailaddress:[email protected](A.García-Salido).

2341-2879/©2020Asociaci´onEspa˜noladePediatr´ıa.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALABRASCLAVE Síndromeinflamatorio multisistémico;

Pediatría;

SARS-CoV-2

Documentoespa˜noldeconsensosobrediagnóstico,estabilizaciónytratamientodel síndromeinflamatoriomultisistémicopediátricovinculadoaSARS-CoV-2(SIM-PedS) Resumen Sehadescritounnuevosíndromeinflamatoriomultisistémicopediátricovinculado aSARS-CoV-2(SIM-PedS).Estecuadropresentaunaexpresividadclínicavariableyseasociaa infecciónactivaorecienteporSARS-CoV-2.Enestedocumentoserevisalaliteraturaexistente porpartedeungrupomultidisciplinardeespecialistaspediátricos.Posteriormenteserealizan recomendacionessobreestabilización,diagnósticoytratamientodeestesíndrome.

© 2020 Asociaci´onEspa˜nola de Pediatr´ıa. Publicado porElsevier Espa˜na, S.L.U. Este es un art´ıculoOpenAccessbajolalicenciaCCBY-NC-ND(http://creativecommons.org/licenses/by- nc-nd/4.0/).

Introduction

Itisknowninfectionbythenovelcoronavirus(SARS-CoV-2) inthepaediatricpopulationisusuallymild.^1,2InSpain,pae- diatricpatientsagedlessthan15yearsaccountfor0.4%of hospitaladmissions,0.7%ofintensivecareunitadmissions and0.15‰ofdeathstodate.¹However,sincethebeginning of May 2020, a small number of paediatric patients have developed a hyperinflammatory syndrome witha variable presentation.³ This syndrome is characterised by clinical andlaboratoryfeaturessimilartothosefoundinKawasaki disease (KD), toxic shock syndrome (TSS) or macrophage activationsyndrome(MAS).^4---7Officialhealthagencies,such astheCentersofDiseasePrevention andControl(CDC) of the United States, the World Health Organization or the RoyalCollegeofPaediatricsandChildHealth(RCPCH)have defineditsgeneralcharacteristics.^5---7

Thisnovelsyndromeseemstobeassociatedwithactive or recent infectionby SARS-CoV-2.Mostaffected patients have positive IgG antibody tests and elevated inflamma- tory markers, which suggests immune dysregulation as opposed to a direct pathogenic effect of the virus.^6,7 In this document, we will use the term paediatric multisys- tem inflammatorysyndrome --- temporally associatedwith SARS-CoV-2(PIMS-TS)torefertothiscondition,alsoknown widely as multisystem inflammatory syndromein children (MIS-C).

Definitionsanddifferentialdiagnosis

The definition of PIMS-TS differs slightly between these public health agencies (Table 1).^4---6 This diagnosis should be contemplated in areas with a current or recent high incidence of cases of SARS-CoV-2 or coronavirus disease 2019(COVID-19).⁸Ithassignificantoverlapwiththediffer- entclinical formsofKD(complete KD,incompleteKD,KD shock syndrome [KDSS]). Therefore,some experts recom- mendconsideringPIMS-TSinpatientsmeetingthediagnostic criteriaforanyoftheformsofKD.⁹

The following features are particularly relevant for suspicion of PIMS-TS: diagnostic criteria for complete or incompleteKDatanyage,presenceofgastrointestinalman- ifestations(vomiting, nausea,abdominalpain,diarrhoea), elevation of acute phase reactants, shock, hypotension,

myocardialdysfunction,lymphopenia,anaemiaandthrom- bocytopenia(Table2).¹⁰

Thedifferentialdiagnosisshouldalwaysincludethefol- lowing:

- Bacterialsepsis.

- Otherviralinfections(adenovirus,enterovirus,measlesin unvaccinatedindividuals).

- Acuteabdomen.

- StreptococcalorstaphylococcalTSS.

- Myocarditiscausedbyothermicroorganisms.

- KDunrelatedtoSARS-CoV-2.

- Drug hypersensitivity reaction (Stevens-Johnson syn- drome).

- Othersystemicrheumaticdisorders(systemiconsetjuve- nile idiopathic arthritis and other autoinflammatory or autoimmunediseases).

- Primaryorsecondaryhaemophagocyticlymphohistiocyto- sis(HLH).

Initialstabilizationandcare

InitialcareandstabilizationwillfollowtheABCDEapproach.

The airway is usuallypatent, unless the patientpresents withalteredlevelofconsciousness.Administersupplemen- taloxygenasneeded.Monitortheoxygensaturation(SatO2), along withthe expired carbon dioxide(EtCO2) when pos- sible. Preparethe equipment anddrugs needed for rapid sequenceintubation.

Monitor the respiratory rate (RR). Tachypnoea without breathingdifficulty isa possible featurein thesepatients (ascompensationofthemetabolicacidosisassociatedwith shock). Rule out lung infection or cardiogenic pulmonary oedema.Measure and document theblood pressure(BP), heart rate (HR) and peripheral perfusion (capillary refill time,skintemperatureandcolour,perfusionindex).Estab- lishperipheralvascular access(ideally,2lines).Incase it cannot be establish, consider a peripheral catheter (ide- ally,2).Ifthisfails,considerplacementofanintraosseous catheter.Fig. 1 presents the recommended algorithm for managementof haemodynamicsupport. The level ofcon- sciousness,pupillaryreflex,glycaemiaandseverityofpain must beassessed in every patient.It is also necessary to 116.e2

Haemodynamic support algorithm

Fluid resuscitation

Fluid-refractory shock

Catecholamine-resistant shock

Adequate protection against infection by SARS-CoV-2 (PPE)

Fluid resuscitation with 10-20 mL/kg (maximum 40 mL/kg) until target reached Discontinue in case of clinical worsening or signs of fluid overload

Consider early echocardiographic assessment

Clinical goals: attain normal MAP (55 + 1.5 x age in years), HR, perfusion, level of consciousness, diuresis + BE and lactate

Administer empiric antibiotherapy until sepsis is ruled out A, B, C, D, E assessment

Identify shock/ perfusion changes/altered level of consciousness/PIMS-TS symptoms Conventional oxygen with surgical mask if possible/non-rebreather bag mask/HFOT/establish

IV /intraosseous (IO) access

Epinephrin at 0.05-0.3 µg/kg/min IV/IO If signs of warm shock, administer

norepinephrine > 0.05 µg/kg/min

Consider intubation Consider central venous catheter placement

Intubation, establishment of central arterial and venous access, if not done before Advanced monitoring: cardiac index (CI) and resistance index (SVRI)

Consider corticosteroids Objectives:

Clinical 1.

2.

3. CI = 3.3-6 L/min/m and SVRI = 80 x (MAP – CVP)/CI = 800 – 1600 dyn • s/cm5/m2

MAP – CVP normal for age, SvCO2 > 70%

Normal BP cold shock Despite epinephrine Myocardial

dysfunction/SvCO2 < 70%

with Hb > 10 g/dL 1. Add milrinone

2. If not responding, consider levosimendan

3. If CI < 3.3 with high systemic resistance: add nitroprusside

Low BP cold shock Despite epinephrine SvCO2 < 70% with Hb > 10 g/dL 1. Add norepinephrine to attain normal diastolic BP

2. If CI < 3.3/myocardial dysfunction:

add dobutamine, enoximone, levosimendan or milrinone

Low BP warm shock SvCO2 < 70% despite optimizing volume status and noradrenaline 1. Add vasopressin/terlipressin 2. If CI < 3.3/myocardial dysfunction, add epinephrine, dobutamine, milrinone or levosimendan

Refractory shock

Consider ECMO

Fig.1 Algorithmforhaemodynamic supportinpatientswithPIMS-TS.BE,baseexcess;CI,cardiacindex;CVP,centralvenous pressure;ECMO,extracorporealmembraneoxygenation; HFOT,high-flow oxygentherapy; HR,heart rate;IV, intravenous;MAP, mean arterialpressure;PPE,personalprotective equipment;RR, respiratory rate;SBP,systolic bloodpressure;SvCO2,central venousoxygensaturation;SVRI,systemicvascularresistanceindex.

AdaptedfromtheAmericanCollegeofCriticalCareMedicineClinicalPracticeParametersforHemodynamicSupportofPediatric andNeonatalSepticShock.CriticalCareMedicine2017;45:1062-1093.

Table1 CasedefinitionofPIMS-TSoftheWorldHealthOrganization(WHO),CentresforDiseaseControlandPrevention(CDC) andRoyalCollegeofPaediatricsandChildHealth(RCPCH).

WHO Patientaged≤19yearswithfever≥3days ANDatleast2ofthefollowingcriteria:

Rash,bilateralnonpurulentconjunctivitis,ormucocutaneousinflammationsigns(oral,hands,orfeet) Hypotensionorshock

Cardiacdysfunction,pericarditis,valvulitis,orcoronaryabnormalities(includingechocardiographic findingsorelevatedtroponin/BNP)

Evidenceofcoagulopathy(prolongedPTorPTT;elevatedD-dimer) Acutegastrointestinalsymptoms(diarrhoea,vomiting,orabdominalpain) ANDelevatedmarkersofinflammation(eg,ESR,CRP,orprocalcitonin)

ANDnootherobviousmicrobialcauseofinflammation,includingbacterialsepsisand staphylococcal/streptococcaltoxicshocksyndromes

ANDEvidenceofSARS-CoV-2infection(positiveSARS-CoV-2RT-PCR,serology,antigentest)orcontactwith anindividualwithCOVID-19

CDC Patientaged<21withfever>24h

ANDevidenceofseverediseaserequiringhospitaladmissionwithinvolvementofmorethan2organsor systems(cardiovascular,respiratory,haematologic,gastrointestinal,dermatologicorneurologic) laboratoryevidenceofinflammation(elevatedCPR,ESR,fibrinogen,PCT,D-dimer,ferritin,LDHorIL-6, neutrophilia,lymphopeniaorhypoalbuminaemia)

ANDlackofalternativeplausiblediagnosis

ANDevidenceofrecentorcurrentSARS-CoV-2infectionorexposure(positiveSARS-CoV-2RT-PCR,serology, antigentest)orofCOVID-19exposurewithinthe4weekspriortotheonsetofsymptoms

RCPCH,UK Persistentfever

ANDsignsofinflammation(neutrophilia,elevatedCRPandlymphopenia)

ANDevidenceofsingleormultipleorgandysfunction(shock,cardiac,respiratory,renal,gastrointestinalor neurologicdisorders),withadditionalfeatures(seetableinthecasedefinition).Itmayincludechildren fulfillingfullorpartialcriteriaforKawasakidisease

Exclusionofanyothermicrobialcause,includingbacterialsepsis,staphylococcalorstreptococcalshock syndromes,infectionsassociatedwithmyocarditissuchasenterovirus

SARS-CoV-2PCRtestingmaybepositiveornegative

BNP,B-typenatriureticpeptide;COVID,coronavirusdisease;CRP,C-reactiveprotein;ESR,erythrocytesedimentationrate;IL-6,inter- leukin 6;LDH, lactate dehydrogenase; PCT, procalcitonin;PPT, partial prothrombintime; PT, prothrombin time; RT-PCR, reverse transcription-polymerasechainreaction.

Table2 Mostfrequentclinicalmanifestationsandlaboratoryfindings.

Clinicalmanifestations

Fever(innearly100%ofcases);fever>3days(ashorterdurationdoesnotruleoutPIMS-TS) Gastrointestinalsymptoms(>50%):abdominalpain,vomiting,diarrhoea

Rash(scarlatiniformrash,erythroderma,erythemamultiforme,livedoreticularis),non-exudativeconjunctivitis, mucosalabnormalities,peripheralabnormalities(>2/3patients)

Shock,tachycardia,hypotension,hypoperfusion(approximatelyhalfofpatients) Headache,meningism,confusion(10−20%)

Respiratorysymptoms:cough,dyspnoea(30-60%) Laboratoryfindings

Completebloodcount:leucocytosiswithlymphopenia,neutrophiliaandthrombocytopenia

Inflammatorymarkers:elevationofCRP,ESR,ferritin,fibrinogen,LDH,IL-6.NormalorelevatedPCTnormal(inabsence ofbacterialinfection)

Coagulation:fibrinogen,D-dimerelevation

Bloodchemistry:hyponatremia,hypoalbuminemia,transaminaseelevation(ALT,AST)

Cardiacmarkers:highelevationofNT-proBNP(>200ng/L),elevationofcardiacenzymes(troponin-I,CK-MB)

ALT,alanineaminotransferase;AST,aspartatetransaminase;CK-MB:creatinekinasemyocardialband;CPR,C-reactive protein;ESR, erythrocytesedimentationrate;IL-6,interleukin6;LDH,lactatedehydrogenase;NT-proBNP,N-terminalpro-B-typenatriureticpeptide;

PCT,procalcitonin;PPT,partialprothrombintime;PT,prothrombintime.

Table3 Recommendeddiagnostictestsandmostfrequentabnormalities.

Test Abnormalities

Completebloodcount Leucocytosis(usually<20000/mm³)withlymphopenia Anaemiavariable

Mildthrombocytopenia(normally>50000/mm³)

Electrolytepanel Hyponatraemia

Liverpanelandalbumin Transaminaseelevation Hypoalbuminemia

Cardiacmarkers^a Elevationofpro-BNP(>35pg/mL)orNT-proBNP(>125pg/mL)andultrasensitive troponin(>14ng/L)

Bloodgases Metabolic/respiratoryacidosis,dependingonclinicalcondition

Inflammatorymarkers^a ElevatedCPR(>20mg/L),PCT(>0.5␮g/mL),IL-6(>8.5pg/mL)andferritin(>

120mg/dL)

Coagulationstudy Increasedfibrinogen(>400mg/dL)

SignificantD-dimerelevationD(>500ng/mL) AbnormalPT/PPT

Bloodculture Usuallynegative

Other Coinfections

[0,1---2] Urineculture

[0,1---2] PCRrespiratorypanelinnasalaspiratesample [0,1---2] Stoolculture/PCRfordetectionofpathogensinstool

CPR,C-reactiveprotein;IL-6,interleukin6;PCT,procalcitonin;PPT,partialprothrombintime;PT,prothrombintime.

a Suggestedvalues,considerthereferencevaluesusedatthehospital.

assess for the presence of exanthema and petechiae and measurethetemperature.¹¹

Any patient with suspected PIMS-TS should be trans- ferredtoahospitalallowingmultidisciplinarymanagement.

In severe cases, transfer to a hospital with a paediatric intensivecareunit(PICU)isrecommended.^4---6,12

DiagnostictestsunrelatedtoSARS-CoV-2

Alternativeinfectiousagentsthatcouldbecausingthedis- easemust beruledout.Table3details therecommended diagnostictestsandthemostfrequentabnormalitiesfound in patients with suspected PIMS-TS.^10---13 Patients with shockmaypresentwithlymphopenia,anaemiaandthrom- bocytopenia and increased levels of ferritin, LDH and D-dimer D (DD).¹⁰ Patients with coronary aneurysms may present with even lower white blood cell and lympho- cytecountsassociatedwithelevationofC-reactiveprotein (CPR).^10---13,14

Compared to KD or TSS, PIMS-TS usuallypresents with a greater elevation of inflammatory markers.¹⁰ Specifi- cally,comparedtocompleteKD,PIMS-TSisassociatedwith higher levelsof CRP,ferritin, inflammatory cytokines and N-terminalprob-typenatriureticpeptide(NT-proBNP)and ahigherfrequencyoflymphopeniaandthrombocytopenia, withnodifferencesinDDlevels.^14---17

Another frequent feature is an increased neutrophil- lymphocyteratio.ThereisadecreaseintheCD4+,CD8+and naturalkiller(NK)Tcellcounts.Thisphenomenoncouldbe associatedwiththeinfiltrationoftheextracellularspaceby theseinnateimmunesystemlymphocytes.¹⁸ Whenitcomes tothecytokines,PIMS-TSmanifestswithelevationofinter- leukin(IL)-1initssolubleform(IL-1␤)andIL-6.^19---21

DiagnostictestsrelatedtoSARS-CoV-2

MostpatientswithPIMS-TS havepositive resultsin oneor morediagnostictestsfordetectionofacuteorpastinfec- tionbySARS-CoV-2.IneverypatientwithsuspectedPIMS-TS, atleast1respiratorysampleshouldbeobtainedtoperform areverse-transcriptasepolymerasechainreaction(RT-PCR) test.Itiswidelyaccepted thatthesamplesthatofferthe highestsensitivityfordetectionofSARS-CoV-2infectionare bronchoalveolar lavageor endotracheal aspiratesamples.

Nasal swab, throat swab or nasal wash samples are also acceptable.^22,23IftheRT-PCRtestisnegativeandtheclini- calsuspicionishigh,werecommendrepetitionofthetestin thenext24---48hours.Incaseofclinicalworseningrequiring invasivemechanicalventilation,werecommendcollection ofanendotrachealaspiratesample.²²

We also recommend serologic testing of all patients, independentlyof RT-PCRtest performance orresults. The yieldofserologyisgreaterafteraminimumof10daysfrom theonsetofsymptoms.Inpatientswithnegativeresultsof bothRT-PCRandserologywithahighclinicalsuspicion,we recommendrepetitionofserologictesting3---4weeksafter admission.Previous studies have reportedthat 26 to55%

ofpatientswithPIMS-TShavepositiveRT-PCRtestsandup to90%havepositiveforIgGantibodytests.^10---17Antibodies can be detected from 10 to 15 daysafter infection, and cumulativeseroconversionpeaksatabout16---21days.^22,23

Imagingtests

Performanceofplainchestradiographoralungultrasound scanis indicatedin patientswithrespiratorysymptomsor to assess placement of indwelling devices (endotracheal tube or central lines).²⁴ The chest radiograph can detect

HOSPITAL MANAGEMENT OF PATIENTS WITH PIMS-TS

CHECK-IN AND ADMISSION

ISOLATION PRECAUTIONS

CARDIAC ASSESSMENT

ADMISSION TO PICU

Echocardiogram ECG Markers NORMAL

ELEVATED MARKERS CORONARY ECTASIA GIANT ANEURYSM

IF THERE IS NO PICU, CONSIDER TRANSFER IN CASE OF…

DISCHARGE CRITERIA

MONITORING SUPPORTIVE

CARE CARDIAC ASSESSMENT

• Patient identification • Contact and droplet • Pulse oximetry • Antipyretics

• Antibiotherapy

• Fluid therapy

• Oxygen therapy

• Heparin and aspirin

• Immunoglobulin and/or corticosteroids

• Respiratory rate

• Blood pressure and urine output

• Individual room

• 1 accompanying person

• Use of surgical masks

• Use of personal protective equipment

• Take vital signs

• Check vascular access

lines, catheters etc. • Early warning scores

• Heart rat

Consider in 1-2 wk

Repeat assessment in 24 h

Consider CT angiography Every 2-3 days → weekly

In 72 h In 72 h

• Echocardiogram

• Electrocardiogram

• Cardiac markers (CK-MB, troponin, NT-proBNP)

• Haemodynamic instability or signs of hypoperfusion

• Vasoactive support

• Myocardial damage

• Altered consciousness

• Non-invasive ventilation

• Mechanical ventilation

• Progressive organ dysfunction

• Worsening or lack of improvement at 8 hours from admission

• Progressive organ dysfunction

• Altered level of consciousness

• Need of respiratory support beyond oxygen with nasal prongs

• Afebrile for 48 hours

• Improvement of symptoms and laboratory parameters

• Normal cardiac function

• Absence of severe complications

• Assess epidemiological conditions and risk of transmission

• Does not need supplemental oxygen

• Haemodynamic instability or hypoperfusion. Myocardial damage confirmed by echocardiogram

Fig.2 HospitalmanagementandtreatmentofPIMS-TS.

abnormalities in a high percentage of cases.^8---25 Some of theradiographicfeaturesreportedintheliteratureincluded pulmonary infiltration, patchy consolidation, ground glass opacities or interstitial changes, atelectasis and pleural effusion. The lung ultrasound scan can detect patterns compatible with pneumonia or a buildup of fluid in the lungs.Routineperformanceofathoraciccomputedtomog- raphy(CT)scanisnotrecommended,exceptinpatientswith complicated pneumonia, significant worseningor whoare immunocompromised.

An abdominal ultrasound or CT scan is indicated in patientswithmanifestationssuggestiveof acuteabdomen to detect potential complications and assess the need of surgery.Ileocolitishasbeendescribedinsomepatientswith PIMS-TS.

Cardiacfunctiontests

Werecommendperformanceofanechocardiographicstudy in allpatients withPIMS-TS. Echocardiographic abnormal- ities are not usually found in patients with mild forms.

The abnormalities described inpatients withmoresevere disease include leftventricular systolic dysfunction,right ventricular dysfunction, mitral valve insufficiency, peri- cardial effusion and coronary artery (CA) dilatations or aneurysms.¹³TheassessmentoftheCAsincludescalculation ofCAsizez-scoresandclassificationbasedontheNational ConsensusDocumentonKawasakiDisease.²⁶Ahighpropor- tionofpatientsexhibitelevationoftroponinIorT(55-68%) andBNP/NT-proBNP(83-100%),withsignificantlyhigherval- uescomparedtopatientswithshock.^3,10---19

The electrocardiographic features are generally non- specific. Patientswith PIMS-TS may exhibit abnormalities suggestiveofmyocardialinvolvement,suchaslowvoltage, STsegmentabnormalitiesandprolongationoftheTwaveor theQTinterval.Differentdegreesofatrioventricularblock andsupraventricularandventriculararrhythmiashavealso

beenreported.^9---13Cardiovascularmagneticresonanceimag- ing(MRI)isnotindicatedduringtheacutephaseofdisease.

Performanceof MRIshouldbecontemplatedbasedonthe suspicionofcardiacinvolvement,patientsafetyduringthe testandavailabilityofMRIinthehospital.

Hospitaladmissionandcare

Allpatients withsuspectedPIMS-TSshouldbeadmittedto thewardforobservation andtreatment,ifapplicable.All effortsmustbemadetokeepthestaffthatentersincontact withthe patient to the minimum necessary. The staff in contactwithapatientwithPIMS-TSmustwear,atminimum, aFFP2mask, disposablegowns,glovesandeyeprotection untilthepatienthasatleast2negativeRT-PCRtestresults.

A high percentage of patients will have negative RT-PCR results.This is indicative of a low or norisk of transmis- sion.In patients withpotential active infectiondespite a negativeRT-PCRtest,asecond RT-PCRtestmustbedone.

Fig.2summarizes therecommendationsonisolationmea- sures,monitoringandtreatment.

Criticalpatients

If admission to PICU is necessary, the patient should be placedin anisolation room,preferablyone withnegative pressure.²⁷ If performance of aerosol-generating proce- duresisnecessary,the carestaffwillwearFFP3masks,a full-facepowered-air-purifyingrespirator,eyegoggles,dis- posablecoverallsorcaps,awater-resistantdisposablegown or, if the gown is not water-resistant, a water-resistant apron, and gloves. If intubation is required, use double gloves.

Thepatientwillbeaccompaniedbyonefamilymember or caregiverthat willadheretothe isolationand hygiene measuresasdirectedby staffandwillwear,at minimum,

a surgical mask, gown and gloves. If the RT-PCR is nega- tive,modificationoftherequiredprotectivemeasureswill beconsidered,alwaysmaintainingcontactanddropletpre- cautions.

PatientsadmittedtothePICUwillbemonitoredperpro- tocol according totheircondition and diseaseseverity. In severecases,considerearlyestablishmentofcentralarte- rialandvenousaccess.²⁸

Respiratorysupport

Respiratorydistressoccursin70%ofcases,andtheneedof respiratorysupportis usuallyassociated withcardiovascu- lar involvementor haemodynamic instability.²⁴ Administer supplementaloxygenthroughnasalprongsunderasurgical mask tomaintaintheSatO2in the94to98%range.Ifthis isnotsufficientduetotheconditionofthepatientor the arterialbloodgasvalues,considerhigh-flowoxygentherapy (HFOT) or non-invasive ventilation (NIV). Respiratory sup- port must always be providedwhile maintaining isolation andprotectivemeasures.

In case ofhypoxaemiain absenceofhypercapnia, con- siderinitiationofHFOT.

IfHFOTisineffectiveorasanalternativeoption,initiate NIVwithcontinuouspositiveairwaypressure(CPAP)withan oronasalmask,full-facemaskorhelmet(thelatterprovides thebestseal).Ifthepatientalsohashypercapnia,consider bilevelpositiveairwaypressure(BIPAP).²⁹

Ifthereis noclear improvementin clinicalparameters (HR, RR,respiratorydistress)andoxygenation(PaO2/FiO2, SatO2/FiO2) within a few hours, we recommend early intubation. Early intubation should also be considered in case of altered level of consciousness or fluid-refractory or catecholamine-resistant shock.²⁹ We recommend the following initial settings for respiratory support: tidal volume of 4 to 8mL/kg, identification of the optimal positiveend-expiratorypressuretoachieveadequatealve- olar recruitment,plateaupressuresofless than30cmH2O and a driving pressure of less than 15 cmH2O.²² If the patientdevelopsmoderate-to-severeacuterespiratorydis- tress,followtherecommendationsforlungprotectionwith permissivehypercapnia,useofthepronepositionandneu- romuscularblockade. Nitric oxideis reserved for patients with refractory hypoxaemia, especially if it is associated withpulmonaryhypertension.³⁰

Haemodynamicsupport

Haemodynamic instability is usuallyassociated with vaso- plegicsyndromeorheartfailure.^5,31 Fig.1summarisesthe recommendationsforhaemodynamicsupportanditsgoals.¹¹ In patients with heart failure administer epinephrine and consider additionof milrinone or, in case of moderate to severeheartfailure,levosimendan.

Pharmacotherapy

Immunomodulatory therapy will begiven with a stepwise approach, startingwithintravenousimmunoglobulin(IVIG)

or corticosteroids asfirst-line treatment.^24---32 In severe or refractorycases,werecommendcombiningboth.

Immunomodulatorytherapy

Intravenousimmunoglobulin

Intravenous immunoglobulin shouldbe given at a dose of 2g/kg, especially in patients meeting the criteria for KD

orTSS.^12---17 Haemodynamicinstabilitycan betreatedwith

1g/kg/dayfor2days.Ifthefeverpersists,consideradmin- istrationofaseconddose36hafterthefirst.^17---31

Systemiccorticosteroidtherapy

Intravenouscorticosteroidtherapyisindicatedbothasthe firststepoftreatmentandinpatientsthatdonotrespond totheinitial dose of IVIG. Early administrationshould be consideredinpatientswithriskfactorsfordevelopmentof coronaryaneurysms or laboratory results compatiblewith MAS.^20---26

- Mild-moderate disease: intravenous methylprednisolone at 1−2mg/kg/day for 3−5 days followed by discon- tinuation of methylprednisolone. In patients requiring treatment for 6 or more days or withpersistent symp- tomsorelevationofinflammatorymarkers,stepuptooral prednisonewithtaperingoffover2---3weeks.

- Severe disease (shock, especially in patients requir- ing high doses of inotropes/vasopressors): intravenous methylprednisolone at 1−2mg/kg/day for 3−5 days or intravenousmethylprednisoloneat30mg/kg/dayfor1---3 days(maximumof1g).Ifthepatientrespondswell,con- tinue treatmentwithoral prednisoneat 1−2mg/kg/day withtaperingofthedoseuntiltheinflammatorymarkers normalize.

- Kawasaki-like disease:combine corticosteroids and IVIG inpatientsathighriskofIVIGresistance(male,age<12 months,CPR>100mg/L,plateletcount<300000/mm³, alanineaminotransferase >100IU/L,neutrophilcount>

80%,sodium<133mmol/L).⁹

Interleukin-1inhibitors

An IL-1 receptor antagonist (anakinra) has been used successfullyinpatientswithseverepneumoniaandhyperin- flammationassociatedwithSARS-CoV-2infection,³³MASand KDrefractorytoIVIG/corticosteroidtherapy.Thus,itmaybe beneficialtopatientswithPIMS-TS.Itisconsidered asafe drugonaccountofitsshorthalf-life,quickactionandinfre- quentassociationwithbacterialsuperinfections.Althoughit isdistributedinsyringesforsubcutaneousadministration,it hasbeendeliveredintravenouslyinseverelyillpatients.^5---10 Thedurationoftreatmentwouldbeof5---14daysdepending ontheclinicalresponse(Table4).

Tumournecrosisfactoralphainhibitors

Infliximabhasbeenproposedasanalternativetreatmentin patientswithIVIG-resistantKD,butinclinicaltrials,whileit achievedquickerimprovementofsymptomsandlaboratory parameters, it did not improve long-term cardiovascular

Table4 Dosage,precautionsandrouteofadministrationofimmunomodulatordrugs.

Drug Dose Dilution Adverseeffects Precautions

Anti-IL-1 Anakinra Subcutaneous 2mg/kg/daywith progressiveincreaseto 8mg/kg/dayevery12h (maximumof400mg/day) Intravenous

2options:

1)similartosubcutaneous 2)continuousinfusion

<20kg:single2mg/kg dose,followedby 0.02ml/kg/h

>20kg:single2mg/kg dose,followedby 0.01mL/kg/h

Maximumdose400mg/day

Ifintravenous, dilutewithPSto concentrationof 4−36mg/mL

Localreactionat injectionsite, flu-likeillness, neutropenia, headache,myalgia, highervulnerability toinfection

Localcoolingat injectionsite.

Monitortransaminase levels

Anti-TNF-␣ Infliximab 5mg/kg Dilutethe

reconstituteddose in250mLof normalsaline.

Administerover2 h

Anaphylaxis, infection

Consider

premedicationwith antihistamineand corticosteroidto preventinfusion reaction Anti-IL-6 Tocilizumab Singledose

<30kg:12mg/kg

>30kg:8mg/kg (maximumof800mg)

<30kg:dilutein 50mLofnormal saline

>30kg:dilutein 100mLofnormal saline

Administerover1 h

Neutropenia, thrombocytopenia, hypertransami- nasaemia, infections, intestinal perforation

Closemonitoringof concurrentinfections (preventCPR elevation)

Donotuseifplatelets

<100000,neutrophils

<500orAST/ALT>3 timesthebaseline

aIfthedoseofanakinrais>100mg/day,administerevery8-12horascontinuousinfusion.

bTheintravenousrouteispreferredfordoses>100mg/dayorinpatientswithaplateletcount<20000,haemorrhagiccomplicationsor severeoedema.

outcomes.^10,11Therearefewdataonitsuseinpatientswith PIMS-TS(Table4).

Interleukin-6inhibitors

Tocilizumab is approved for treatment of CAR T-cell- associatedcytokinereleasesyndromeandseveraltrialsare currently underwayof itsuse inpatients withSARS-CoV-2 pneumonia.IthasbeenusedinselectcasesofPIMS-TS,but theuseoftocilizumabinpatientswithKDcouldaccelerate thedevelopmentofcoronaryaneurysms^34,35(Table4).

Antiviraltherapy

At the time of this writing, there is no evidence on the efficacy or safety of any antiviral used for treatment of SARS-CoV-2infectioninchildren.Werecommendagainstthe useofhydroxychloroquine^36,37 or hydroxychloroquinecom- bined with azitromicin.^37,38 While the role of SARS-CoV-2 inthedevelopmentofPIMS-TSremains unclear,treatment withremdesivir should becontemplatedin case of active infection, high suspicion of SARS-CoV-2 or severe disease

(Table 5). Remdesivir can be administered to paediatric patientsinthecontextofaclinicaltrialorafterobtaining authorizationforexpandedaccess.³⁹

Antithromboticandantiaggreganttherapy

Indicationsforlowmolecularweightheparin

Considerprophylaxis withlowmolecularweightheparinin thefollowingcases³⁹:

a) DD≥6timestheupperlimitofnormal.

b) Immobilizedpatient.

c) Presenceofgiantaneurysms.

d) Severe left ventriculardysfunction(ejection fraction<

30%).

e) Personalorfamilyhistoryofthromboembolism.

f) Personal historyofarterialischaemia(peripheral,coro- naryorcerebrovascular).

Administersubcutaneousenoxaparinat1mg/kg/day(in case of renal insufficiency with a glomerular filtration rate < 30mL/min/m², dose of 0.25mg/kg/12h). Measure anti-factor Xa levels at 48−72h (recommended range,

Table5 Dosageandadverseeffectsofantiviraltherapy.

Drug Indication Dose Adverseeffects Monitoring

Remdesivir (intra- venous)

Clinicaltrial/

compassion- ate

use

Weight:2.5-40kg

Loadingdose:5mg/kg/24h(1 bolus)

Maintenancedose:

2.5mg/kg/24h Weight≥40kg

Loadingdose:200mg/24h(1 bolus)

Maintenancedose:

100mg/24h

Hypertransaminasaemia Alteredrenal

function

Transaminases Renalfunction

0.3−0.49). Continueuntilsymptomsresolve andDDlevels havenormalizedbasedonthereferencevaluesusedatthe specifichospital.

In patients with thromboembolism or suspected deep veinthrombosis,administerenoxaparinatadoseof1mg/kg every 12h delivered subcutaneously. When given in anti- coagulant doses (0.5---1 anti-Xa), measure anti-Xa at 48h (adjustdosebasedonreferencevalue).Maintainthroughout thehospitalstayandconsultwithhaematologydepartment priortodischarge.

Acetylsalicylicacid

Thereare2possibleindications:

- Anti-inflammatory:patientswithPIMS-TSmeetingthecri- teriaforcompleteorincompleteKD.Prescribealongwith IVIG.Starttreatmentwithoralacetylsalicylicacid(ASA)at adoseof30−50mg/kg/daygivenat6-hintervalsuntilthe patientisafebrilefor48h.Atthistime,reducetoadose appropriateforantiaggreganttherapyof3−5mg/kg/day, alsobytheoralroute.Maintainthisdoseuntil6---8weeks fromtheonsetofsymptomsandafterverifyingnormaliza- tionoftheplateletcount,levelsofacutephasereactants andechocardiographicparameters.²⁶

- Antiaggregant:inpatientswithPIMS-TSthatareseverely ill, have aneurysms, with clinical or laboratory find- ingsindicativeofinflammation orthrombocytosiswitha plateletcountgreaterthan700000/mm³,consideradmin- istration of ASA at an antiaggregant dose for 6 weeks (confirm normalization of echocardiographic findings at theendofthisperiod).Thisrecommendationisbasedon thedescriptionofcoronaryabnormalitiesinpatientsthat donotmeetthecriteriaforcompleteorincompleteKD.¹⁰

RescuetherapywithECMO

Patients with PIMS-TS may be eligible for extracorporeal membrane oxygenationiftheyfailtorespondtomaximal conventionaltherapies,theirconditionisdeemedreversible and they have no absolute contraindications for ECMO.⁴⁰ These patients must be referred before their condition precludes conventionaltransport.When thelatteroccurs, consider transport under ECMO with cannulation at the referringhospitalperformedbyqualifiedstaff.

Dischargeandfollowup

Assess the potentialrisk of transmissionof SARS-CoV-2 in thehousehold.PatientswithanegativeRT-PCRtestanda positiveIgGtestarenotconsideredinfectious. Also,posi- tivedetection ofIgG antibodies combinedwithapositive RT-PCRtestor seroconversionafternegativePCRresultsis currentlyinterpreted asdetection of dead viralremnants thatarenotinfectious.Werecommendfollowupbyamulti- disciplinaryteamattheoutpatientlevel,withinvolvement oftheprimarycarepaediatrician(Fig.2).

Conflicts of interest

Jordi Antón has received research grants, speaker and consultant fees and financial support to attend medical congressesfromSobiandRoche.EsmeraldaNú˜nezhaspar- ticipated in educational activities sponsored by AbbVie, RocheandSobi.InmaculadaCalvohasparticipatedineduca- tionalactivitiessponsoredbyNovartis,AbbVie,Sobi,Roche and GSK and collaborated in workshops offered by GSK, NovartisandSobi.JavierPérez-LescurePicarzohasreceived feesfromMSDfordeliveryofeducationalprogrammes.The restoftheauthorshavenoconflictsofinteresttodeclare.

Acknowledgments

Wethankallhealthcareprofessionalsinvolvedinpaediatric care,patientsandtheirfamilies.

Appendix A. Members of the Working Group on Paediatric Multisystem Inflammatory Syndrome Temporally Associated with SARS-Cov-2 of the Asociación Espa˜ nola de Pediatría

SylviaBelda Hofheinz (SECIP, Hospital Universitario 12 de OctubredeMadrid),InmaculadaCalvoPenadés(SERPE,Hos- pitalUniversitarioyPolitécnicoLaFe),JuanCarlosdeCarlos Vicente (SECIP, HospitalUniversitario SonEspases), Carlos Daniel Grasa Lozano (SEIP, Hospital Universitario La Paz), SusannaHernándezBou(SEUP,HospitalSantJoandeDéu), RosaM. PinoRamírez(SEPHO,HospitalSantJoandeDéu),

EsmeraldaNú˜nezCuadros(SERPE,HospitalRegionalUniver- sitario deMálaga), Javier Pérez-LescurePicarzo (SECPCC, Hospital Universitario Fundación Alcorcón), Jesús Saave- dra Lozano (SEIP, Hospital General Unversitario Gregorio Mara˜nón),DianaSalas-Mera(SECPCC,HospitalUniversitario LaPaz), Enrique VillalobosPinto(SEPHO,Hospital Infantil UniversitarioNi˜noJesús).

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