SARS-CoV-2–Induced Kawasaki-LikeHyperinflammatory Syndrome: A NovelCOVID Phenotype in ChildrenFrancesco Licciardi, MD,a,b Giulia Pruccoli, MD,a Marco Denina, MD,a,b Emilia Parodi, MD, PhD,a,b Manuela Taglietto, MD,b

Sergio Rosati, DVM,c Davide Montin, MD, PhDa,b

abstractWe describe 2 children with persistent fever and profuse diarrhea whodeveloped signs of mucocutaneous involvement (conjunctivitis, fissured lips,skin rash, erythema, and edema of the hands and feet). Blood tests revealedelevated markers of inflammation, lymphopenia, thrombocytopenia, andcomplement consumption. Afterward, diffuse edema with hypoalbuminemiaappeared in the context of a capillary leak syndrome. In both patients,repeated nasal swabs were negative for severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2), but each patient had high titers ofimmunoglobulin G and immunoglobulin M against the SARS-CoV-2 virus. Thenegative PCR results in the presence of immunoglobulin M andimmunoglobulin G suggested that the inflammatory response developed inthe late phase of viral infection, when SARS-CoV-2 was not detectable in theupper airway. In this report, we describe patients with what we propose toname as SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome.SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome seems tobe caused by a delayed response to SARS-CoV-2. It resembles Kawasakidisease complicated by macrophage activation syndrome, although it haspeculiar features, such as prodromal diarrhea, capillary leak syndrome, andmyocardial dysfunction. Intravenous corticosteroid treatment appears to behelpful.

On January 7, 2020, the Chinese Centerfor Disease Control and Preventionisolated a novel coronavirus, severeacute respiratory syndromecoronavirus 2 (SARS-CoV-2), from thethroat swab sample of a patientaffected by interstitial pneumonia.Since then, SARS-CoV-2 cases havespread rapidly throughout China andworldwide, leading the World HealthOrganization to declare a pandemicstate on March 11, 2020. SARS-CoV-2initial symptoms are flulike, such asrhinorrhea, fever, cough, fatigue,myalgia, and, less frequently, diarrhea.In some patients, the infection can leadto severe interstitial pneumonia,

followed by multiorgan failure. Sincethe first reports, the development ofsystemic inflammation has beenproposed as a key factor related to pooroutcomes.1

Preliminary data suggest that SARS-CoV-2 infection in children is usuallymilder. In Italy, as of May 8, 2020,215 665 people were infected withSARS-CoV-2, with ,2% being,18 years of age. Only three pediatricdeaths have been reported.2 Systemichyperinflammation due to SARS-CoV-2infection is currently considered rare inchildren.3 The initial case patientappears to have been a 6-month-oldgirl with SARS-CoV-2 who presented

aDepartment of Pediatric and Public Health Sciences,University of Torino, Turin, Italy; cDepartment of VeterinarySciences, University of Turin, Turin, Italy; and bReginaMargherita Children’s Hospital, AOU Città della Salute edella Scienza di Torino, Turin, Italy

Dr Licciardi gave substantial contribution toconception and design, drafted the article, andreviewed and revised the manuscript; Drs Pruccoliand Denina contributed to conception and design,collected data, described the case reports, andreviewed and revised the manuscript; Drs Parodiand Taglietto collected data, provided iconography,and revised the manuscript; Prof Rosati performedthe serological test and interpretation of data andreviewed the manuscript; Dr Montin supervised datacollection and critically reviewed and revised themanuscript; and all authors approved the finalmanuscript as submitted and agree to beaccountable for all aspects of the work.

DOI: https://doi.org/10.1542/peds.2020-1711

Accepted for publication May 18, 2020

Address correspondence to Giulia Pruccoli, MD,Regina Margherita Children’s Hospital, Piazza Polonia94, 10126 Turin, Italy. E-mail: giu.pruccoli@gmail.com

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

Copyright © 2020 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: The authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors haveindicated they have no potential conflicts of interestto disclose.

To cite: Licciardi F, Pruccoli G, Denina M, et al.SARS-CoV-2–Induced Kawasaki-LikeHyperinflammatory Syndrome: A Novel COVIDPhenotype in Children. Pediatrics. 2020;146(2):e20201711

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with conjunctivitis, polymorphousrash, swollen extremities, andpersistent fever. This patient wastreated as if she had Kawasaki disease(KD) with intravenousimmunoglobulin and acetylsalicylicacid and improved.4

In this report we describe two casesof severe hyperinflammation withsimilar clinical and laboratoryfindings. Neither patient hada positive nasal swab result, but bothhad high immunoglobulin G (IgG) andimmunoglobulin M (IgM) titersagainst SARS-CoV-2.

CASE REPORTS

Patient 1

On April 14, 2020, a 12-year-old boypresented to our emergencydepartment with a 2-day history ofhigh fever and abdominal pain. Hisprevious medical history wasunremarkable. On admission, bloodtests revealed significantlymphocytopenia (lymphocyte levelof 560 cells per mm3) and elevatedlevels of inflammatory markers(Fig 1). A nasopharyngeal swab wasnegative for SARS-CoV-2. A chestradiograph and echocardiogram werenormal, whereas an abdominalultrasound revealed mesentericlymphadenitis. Empirical antibioticswere started, without clinicalimprovement. During the followingdays, he developed mildconjunctivitis, erythema and crackedlips, skin rash, erythema and edemaof the hands and feet, petechialelements (Fig 2), persistent highfever, diarrhea (10–20 times daily),and vomiting. He also developed mildthrombocytopenia, complementconsumption, pleural effusion, weightgain, hypoalbuminemia with mildproteinuria, and an increased ferritinlevel (580 ng/mL). Treatment withmethylprednisolone at 2 mg/kg wasinitiated, with immediatedefervescence, prompt generalimprovement, and normalization ofblood tests. Meanwhile, he developed

cardiac involvement (reduced systolicfunction and pericardial effusion onan echocardiogram, elevated troponinT levels with normal creatine kinasemyocardial band levels, andelectrocardiographic signs ofmyocardial injury). He continuedintravenous corticosteroid for 2weeks, with subsequentnormalization of cardiac function.

Patient 2

On April 18, 2020, a 7-year-old boyarrived in our emergency department

with a 5-day history of fever, nauseaand vomiting, diarrhea, andabdominal pain. He had a previousdiagnosis of periodic fever, aphthousstomatitis, pharyngitis, and cervicaladenitis. Both parents were healthcare workers. The mother hadanosmia and taste dysfunction for 1month. A physical examinationrevealed bilateral conjunctivitis;modest eyelid and scrotal erythema;skin rash on palms and soles, limbs,and back; petechial elements in thelower limbs; dry lips; and de-

FIGURE 1Time line of patients’ symptoms, laboratory findings, and therapy. Laboratory findings are expressedas a ratio of the normal value. Normal values were considered as follows: CRP, 10 mg/L; fibrinogen,300 mg/dL; procalcitonin, 2 ng/mL; lymphocytes, 1500 cells per mm3; platelet count, 250 000/mm3;and ferritin, 150 ng/mL. IV, intravenous; IVIg, intravenous immunoglobulin.

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epithelialized tongue (Fig 2). Bloodtests revealed lymphocytopenia,thrombocytopenia, low C3 and C4levels, hypoalbuminemia, andsignificantly increased levels offerritin (897 ng/mL) and otherinflammatory markers (Fig 1). A chestradiograph and electrocardiogramwere normal, whereas an ultrasoundof the abdomen revealed the presenceof enlarged mesenteric lymph nodes.A nasopharyngeal swab specimenwas negative for SARS-CoV-2. Broad-spectrum empirical antibiotics werestarted. Subsequently, the patientdeveloped hypotension, tachycardia,and tachypnea with oxygendesaturation. Noninvasive respiratorysupport was initiated, and hereceived a crystalloid solution,followed by vasopressors. After fluidresuscitation he developed rightpleural effusion and cardiomegaly.Laboratory and instrumental tests

on hospital day 3 (illness day 7)confirmed the cardiac injury (eg,abnormal troponin T levels, elevatedpro-brain natriuretic peptide levels,and high levels of D-dimer, withreduced systolic function onechocardiography). Treatment wasswitched to intravenousimmunoglobulin at 2 g/kg andmethylprednisolone at 2 mg/kg, andwe continued antibiotic therapy. Thepatient had progressive improvementin clinical condition, laboratory, andimaging results.

Because of the uncertainty about thecause of both of these cases, wemeasured anti–S-specific IgGantibodies to SARS-CoV-2 (LIAISONSARS-CoV-2 S1/S2 IgG [reportedspecificity 98.5%]; DiaSorin, Saluggia,Italy) and found that both patientshad moderate to high positive titersof IgG antibodies versus SARS-CoV-2.A second confirmatory test (Eradikit

COVID19 [reported specificity98.1%]; In3Diagnostic, Turin, Italy)found IgG and IgM antibodiesdirected toward SARS-CoV-2 in bothpatients.

DISCUSSION

These two cases reveal a novel severeinflammatory syndrome that maydevelop in children during the latephase of SARS-CoV-2 infection. SARS-CoV-2 acute infection may mimic KDbecause it may present withpersistent fever, rash, andconjunctivitis; our cases highlight thatSARS-CoV-2 infection may triggera severe inflammatory syndromeeven after seroconversion, when thevirus might not be detected in upperairways.5

These two patients presented withdiarrhea, abdominal pain, high fever,elevated C-reactive protein (CRP) and

FIGURE 2Cutaneous manifestations on day 5 of illness. Patient 1: A, erythema and cracking of lips; B, mild conjunctivitis; C, erythema and edema of the hands; D,petechial elements on feet. Patient 2: E, modest eyelid erythema; F, skin rash on palms; G, cutaneous erythema; H, petechial elements on feet.

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procalcitonin levels, and a lowlymphocyte count (phase1). Despiteappropriate broad-spectrumantibiotic therapy, fever persisted,and mucocutaneous involvementappeared: conjunctivitis, fissuredlips, and acral rash. Both thendeveloped, in phase 2 of their illness,progressive thrombocytopenia, C3and C4 consumption, hepatomegaly,capillary leak syndrome withseverely decreased albuminemia,diffuse edema, and, in one case,severe hypotension requiringfluid resuscitation therapy.Both patients improved afterintravenous corticosteroid therapy,but they developed what appearedto be myocarditis in a thirdphase.

On initial presentation, we believedthey had a gastrointestinal bacterialinfection. In the second phase, bothpatients fulfilled KD diagnosticcriteria. However, they had unusualfeatures, such as the age at diseaseonset and a low platelet count. Thislast finding is not frequent amongpatients with KD, except whenmacrophage activation syndrome(MAS) simultaneously develops. MASis a rare life-threatening complicationof autoinflammatory andautoimmune diseases6 that developsin 1.1% to 1.9% of patients with KD.In 2015 Wang et al7 publisheda report of 8 patients withmacrophage activation syndrome inKawasaki disease (MAS-KD). Allpatients had serum ferritin levels.684 ng/mL and aspartateaminotransferase levels .100 U/L,87.5% had a platelet count of,100000/mm3. Coronaryinvolvement occurred in 25% ofpatients.

MAS-KD has many similaritieswith the clinical picture of ourpatients, although these twopatients had unique features(Supplemental Table 1), suchas the absence of coronaryinvolvement, the developmentof myocardial dysfunction, and

rapidly progressive capillary leaksyndrome.

Our patients did not have a PCRpositive for SARS-CoV-2, but theyhad serological evidence of aninfection by using two differentand highly specific tests. Althoughlittle is known regarding the antibodykinetics, presence of IgM versusSARS-CoV-2 may be consideredas a marker of a recent infection.8

IgM cross-reactivity is improbablebecause nasal swabs were negativefor other coronaviruses (229E, NL63,OC43, and HKU1).

The association betweencoronaviruses and KD washypothesized in the past; inparticular, Esper et al9 in 2005 founda PCR positive for New Havencoronavirus in 8 of 11 infants withclassic KD. Regarding SARS-CoV-2,recent reports suggest that it causescapillary inflammation in the lungsand skin, with complement activationthrough both alternative and lectinpathways.10 A direct viral infection ofthe endothelial cells and diffuseendothelial inflammation can befound in the kidneys, heart, and liverof patients affected by SARS-CoV-211.SARS-CoV-2 shares this capillarytropism with other coronaviruses; inparticular, severe acute respiratorysyndrome coronavirus 1 causescomplement activation in mouselungs, and C32/2 mice haveconsiderably less respiratorydysfunction than wild-type mice.12

These data suggest that themucocutaneous involvement, aswell as the decrease of C3, C4,and platelet counts, may bea consequence ofa microvasculopathy that leads tocapillary leakage. The clinical picturedescribed in our report has manyanalogies with a well-known hyperinflammatory syndrome causedin cats by feline coronavirus:feline infectious peritonitis.Feline infectious peritonitis isa fatal immune-mediated disease;its effusive form is characterized

by fluid accumulation in bodycavities as a consequence of immunecomplex deposition and macrophageactivation.13

Tavazzi et al14 demonstrated thepresence of viral SARS-CoV-2particles in a myocardial biopsy ofa patient with severe myocarditis.SARS-CoV-2 infection can be a triggerfor cardiac injury, secondary toa combination of direct vascular andmyocardial infection plusproinflammatory stimulation, whichcan occur at the same time or evenpost infection.15

We emphasize that heart functionimproved slowly; further follow-upwill be needed to determine if heartfunction will fully recover.

These two patients had mildrespiratory symptoms. In fact, themost significant manifestation wasdiarrhea. We are now evaluatingwhether SARS-CoV-2 is present in thestools, but the validity of such testingis unknown.

CONCLUSIONS

SARS-CoV-2 infection appears to haveled to a late-phase seriousinflammatory syndrome in these twochildren. Although the clinicalpresentation bears some similaritiesto KD-MAS, unusual features, such ascapillary leak, were present. Wepropose that this clinical phenotypebe named SCiKH syndrome (or SARS-CoV-2–induced Kawasaki-likehyperinflammatory syndrome).

ACKNOWLEDGMENTS

We thank Prof Rossana Cavallo andDrs Maria Avolio and Barbara Colittifor performing serological tests; DrsMarisa Zoppo, Federica Mignone,Silvia Garazzino, and Carlo Scolfarofor clinical management of patients;Monica Mantovani for Englishlanguage revision; Cecilia Pruccoli forproviding graphic support; and all theICU and emergency department

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doctors who helped us in treatingthese patients.

ABBREVIATIONS

CRP: C-reactive proteinIgG: immunoglobulin GIgM: immunoglobulin MKD: Kawasaki diseaseMAS: macrophage activation

syndromeMAS-KD: macrophage activation

syndrome in Kawasakidisease

PCR: polymerase chain reactionSARS-CoV-2: severe acute respira-

tory syndromecoronavirus 2

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