Content uploaded by Francesco Bianco
Author content
All content in this area was uploaded by Francesco Bianco on Nov 27, 2020
Content may be subject to copyright.
Prepublication Release
©2020 American Academy of Pediatrics
Multisystem Inflammatory Syndrome in Children: An
International Survey
Carles Bautista-Rodriguez, PhD, Joan Sanchez-de-Toledo, PhD, Bradley C. Clark, MD, Jethro
Herberg, MD, Fanny Bajolle, MD, Paula C Randanne, MD, Diana Salas-Mera, MD, Sandrine
Foldvari, Devyani Chowdhury, MD, Ricardo Munoz, MD13, Francesco Bianco, PhD, Yogen
Singh MD, Michael Levin, PhD, Damien Bonnet, PhD, Alain Fraisse, PhD
DOI: 10.1542/peds.2020-024554
Journal: Pediatrics
Article Type: Regular Article
Citation: Bautista-Rodriguez C, Sanchez-de-Toledo J, Clark BC, et al. Multisystem inflammatory
syndrome in children: an international survey. Pediatrics. 2020; doi: 10.1542/peds.2020-024554
This is a prepublication version of an article that has undergone peer review and been accepted
for publication but is not the final version of record. This paper may be cited using the DOI and
date of access. This paper may contain information that has errors in facts, figures, and
statements, and will be corrected in the final published version. The journal is providing an early
version of this article to expedite access to this information. The American Academy of
Pediatrics, the editors, and authors are not responsible for inaccurate information and data
described in this version.
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Multisystem Inflammatory Syndrome in Children: An International Survey
Carles Bautista-Rodriguez, PhD1,2 *, Joan Sanchez-de-Toledo, PhD3,4 *, Bradley C. Clark, MD5,6,
Jethro Herberg, MD7,8, Fanny Bajolle, MD9,10, Paula C Randanne, MD3, Diana Salas-Mera,
MD11, Sandrine Foldvari1,2, Devyani Chowdhury, MD12, Ricardo Munoz, MD13, Francesco
Bianco, PhD14, Yogen Singh MD15,16, Michael Levin, PhD7,8 #, Damien Bonnet, PhD9,10 **, Alain
Fraisse, PhD1,2 **
1 Paediatric Cardiology Services, Royal Brompton Hospital, Sydney St, London SW3 6NP, United
Kingdom
2 National Heart and Lung Institute, Imperial College, Guy Scadding Building, Dovehouse St, London SW3
6LY, United Kingdom
3 Department of Pediatric Cardiology, Hospital Sant Joan de Deu, Passeig de Sant Joan de Déu 2, 08950
Esplugues de Llobregat, Spain
4 Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh, 4401
Penn Ave, Pittsburgh, PA 15224, United States
5 Division of Cardiology, Children’s Hospital at Montefiore, 3415 Bainbridge Ave, The Bronx,
NY 10467, United States
6 Department of Pediatrics, Albert Einstein College of Medicine, 1400 Pelham Pkwy S, The Bronx,
NY 10461, United States
7 Paediatrics, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London W2 1NY, United
Kingdom
8 Section of Paediatric Infectious diseases, Department of Infectious diseases, Imperial College London,
London W2 1PG, United Kingdom
9 M3C-Necker Enfants Malades, AP-HP, 149 Rue de Sèvres, 75015 Paris, France
10 Université de Paris, 12 Rue de l'École de Médecine, 75006 Paris, France
11 Department of Paediatric Cardiology, Hospital La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain
12 Cardiology Care for Children, 1834 Oregon Pike #20, Lancaster, PA 17601, United States
13 Cardiac Critical Care Medicine, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC
20010, United States
14 AOU Ospedali Riuniti, Via Conca, 71, 60020 Ancona AN, Italy
15 Neonatal Intensive Care Unit, Cambridge University Hospitals, Hills Rd, Cambridge CB2 0QQ, United
Kingdom
16 University of Cambridge School of Clinical Medicine, Box 111 Cambridge Biomedical Campus
Cambridge CB2 0SP, United Kingdom
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
* contributed equally as co-first authors
** contributed equally as co-senior authors
Corresponding author:
Pr Alain Fraisse
Paediatric Cardiology Services, Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK.
Tel : +44 020 7352 8121
E-mail : a.fraisse@rbht.nhs.uk
Conflict of Interest Disclosures
Alain Fraisse is consultant and proctor for Abbott, Occlutech and Medtronic.
Damien Bonnet has served as advisor and steering committee member for Actelion Pharmaceuticals, Bayer
Healthcare, Novartis, Eli Lilly, Bristol Myer Squib and Pfizer. The remaining authors have indicated they
have no conflicts of interest relevant to this article to disclose.
Funding/Support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-
for-profit sectors.
Abbreviations
BNP, brain natriuretic peptide
CAA, coronary artery abnormalities
COVID-19, Coronavirus Disease 19
CRP, C-reactive protein
ECG, electrocardiogram
ECMO, extracorporeal membrane oxygenation
IVIG, intravenous immunoglobulin
KD, Kawasaki Disease
LV, left ventricular
MIS-C, multisystem inflammatory syndrome in children
NT-pro-BNP, N-terminal pro brain natriuretic peptide
PICU, pediatric intensive care unit
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
PIMS-TS, Pediatric Inflammatory multisystem syndrome temporally associated with severe acute
respiratory syndrome coronavirus 2
SARS, Severe Acute Respiratory Syndrome Coronavirus 2
WHO, World Health Organization
Article Summary
International survey about presentation, risk factors and outcome of children diagnosed with multisystem
inflammatory syndrome temporally associated with SARS-CoV-2
What´s Known on This Subject
Clinical, laboratory, imaging and treatment characteristics at presentation of children with multisystem
inflammatory syndrome have been reported in specific cohorts from USA, UK, Italy and France
What This Study Adds
In this international case series, we report the wide clinical spectrum of this emerging disease associated
with SARS-CoV-2 pandemic
Contributors’ Statement Page
Drs Bautista-Rodriguez, Sanchez de Toledo, Foldvari, Singh, Levin, Bonnet and Fraisse conceptualized
and designed the study
Drs Bautista-Rodriguez, Sanchez de Toledo, Clark, Bajolle, Randanne, Salas, Blanco, Singh, Levin, Bonnet
and Fraisse coordinated and supervised data collection.
Drs Bautista-Rodriguez, Sanchez de Toledo, Foldvari, Herberg, Levin, Bonnet and Fraisse carried out the
initial analyses
Drs Bautista-Rodriguez, Sanchez de Toledo, Herberg, Foldvari, Singh, Levin, Bonnet and Fraisse
performed interpretation of data.
Drs Bautista-Rodriguez, Sanchez de Toledo, Levin, Bonnet and Fraisse drafted the initial manuscript.
Drs Bautista-Rodriguez, Sanchez de Toledo, Clark, Herberg, Chowdhury, Munoz, Levin, Bonnet and
Fraisse critically reviewed and revised the manuscript.
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the
work.
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
ABSTRACT
Objective. To describe presentation, hospital course and predictors of bad outcome in Multisystem
Inflammatory Syndrome in Children (MIS-C).
Methods. Retrospective data review of a case series of children meeting published definition for
MIS-C discharged/died between March 1st and June 15th, 2020, from 33 participating European,
Asian and American hospitals. Data was collected through a web-based survey and included
clinical, laboratory, electrocardiographic and echocardiographic findings and treatment
management.
Results. We included 183 patients (109 males [59.6%]; mean age 7.0±4.7 years; black race,
56[30.6%]; obesity, 48[26.2%]) with MIS-C. Overall, 114/183(62.3%) had evidence of SARS-
CoV-2 infection. All presented with fever, 117/183 (63.9%) with gastrointestinal symptoms and
79/183 (43.2%) with shock, that was associated with black race, higher inflammation and imaging
abnormalities. Twenty-seven patients (14.7%) fulfilled criteria for Kawasaki disease. They were
younger with no shock, fewer gastrointestinal, cardio-respiratory and neurological symptoms. The
remaining 77 patients (49.3%) had mainly fever and inflammation. Inotropic support, mechanical
ventilation and ECMO were indicated in 72 (39.3%), 43 (23.5%) and 4 (2.2%) patients,
respectively. A shorter duration of symptoms prior to admission was found to be associated with
poor patient outcome and for ECMO/death, with 72.3% (95% CI 0.56-0.90, p=0.006) increased
risk per day reduction and with 63.3% (95% CI 0.47-0.82, p<0.0001) increased risk per day
reduction respectively.
Conclusion. In this case series, children with MIS-C presented with a wide clinical spectrum,
including KD-like, life-threatening shock and milder forms with mainly fever and inflammation.
A shorter duration of symptoms prior to admission was associated with worse outcome.
INTRODUCTION
After the COVID-19 pandemic hit Europe and America, several centers reported children
presenting with an acute febrile illness accompanied by inflammation, gastrointestinal symptoms
and cardiac complications. This new condition has features similar to those of Kawasaki disease
(KD) and toxic shock syndrome.1-14 Whereas the clinical course of COVID-19 is milder in children
compared to adults, this pediatric inflammatory disease often leads to multiorgan failure and shock
requiring admission to intensive care units.15,16 A case definition of pediatric inflammatory
multisystemic syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) was
proposed by the Royal College of Paediatrics and Child Health in the U.K.17 The World Health
Organization (WHO) and the Centers for Disease Control and Prevention (CDC) in Europe and
USA also issued their overlapping definitions and named the disorder multisystem inflammatory
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
syndrome in children (MIS-C).18-20 The etiopathogenesis of this syndrome and mechanisms of
tissue damage are still unknown.13,21-22
Several initial studies have already been published on PIMS-TS or MIS-C. Multicenter studies
recently described large cohorts of patients from United States centres.8-11 However, despite
worldwide distribution of this new disease, an international study is lacking. Moreover, no
predictors of adverse outcome have been so far identified.
The aim of our study was to describe the presentation and hospital course of MIS-C from an
international cohort, and to identify clinical and biological markers that predicted severe disease.
METHODS
Patients and data collection
We conducted a retrospective data review of children aged 18 years or younger who fulfilled the
case definition of MIS-C17 and had been discharged or died between March 1st and June 15th, 2020
from 13 participating European, Asian and American countries. Participating institutions obtained
local IRB approval with a waiver of informed consent to collect and share deidentified data that
did not include dates of birth, admission, discharge or death.
Patient data and outcomes were collected through a standardized, secured, case-study web-based
survey tool (SurveyMonkey, San Mateo, CA, USA) between May 9th, 2020 and June 16th, 2020.
Patients were included through 3 different types of presentation, which were mutually exclusive:
i) Kawasaki-like, patients with typical KD (presence of at least 4/5 principal features)23,24, ii)
incomplete KD-like, patients not fulfilling typical KD criteria and iii) shock, patients who required
>20 ml/kg fluids bolus at admission. Since there are similarities between MIS-C and Kawasaki
disease, we aimed to compare rates of coronary artery abnormalities (CAA) in MIS-C patients
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
with classical 4/5 diagnostic features of KD, and in those without. We therefore did not use the
presence of CAA as part of the diagnosis of KD in children with incomplete KD-like presentation
with less than 4/5 features. Instead, we explored the occurrence of CAA in both groups.
Patients’ data included age, sex, race, height, weight and comorbidities. Main clinical symptoms
at presentation including fever, mucocutaneous involvement, presence of non-suppurative latero-
cervical lymphadenopathy, conjunctivitis, gastrointestinal, respiratory, cardiovascular and
neurological symptoms were also collected. The time between onset of symptoms and admission
was included in the analysis.
Main laboratory findings including platelet count (x109 per liter), lactate (mmol/L), C-Reactive
Protein (CRP) (mg/L), ferritin (micrograms/L), NT-Pro-BNP and/or BNP (pg/ml), troponin I
(ng/ml) and d-Dimer (ng/ml) reported at patient’s admission were also included in the survey.
Electrocardiogram data at admission including abnormal PR and QT intervals, ST and T-waves
changes were recorded to describe arrhythmia and/or ischemic changes. Echocardiography
findings within 24 hours of admission were reported, including assessment of the coronary arteries,
ventricular function, valvulitis (non-physiological valve regurgitation) and pericardial
effusion.25,26
Information about outcome measures including admission to intensive care unit, inotropic support,
renal replacement therapy, extracorporeal membrane oxygenation (ECMO) and death at time of
admission and during hospital course were also collected, as was information about medications
used to treat the inflammatory syndrome, or potential SARS-CoV-2 infection. Some of the patients
included in this study have been previously published in early reports.6,7,14
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Confirmation of SARS-CoV-2 infection
We surveyed test results from SARS-CoV-2 reverse-transcriptase PCR on nasopharyngeal and/or
oropharyngeal swab samples, and detection of SARS-CoV-2 antibodies (IgM and IgG).
Statistical Analysis
Continuous variables were summarized as either means and standard deviation or medians with
interquartile ranges when appropriate. Student´s t test, the X2 method, or Fisher´s exact test, Mann-
Whitney U, Wilcoxon tests and Kruskal-Wallis were performed when appropriate. We used
multiple logistic-regression analysis to identify independent predictors of bad outcome for those
who deteriorated after admission, as defined by the following: transfer to intensive care,
mechanical ventilation, inotropic support, renal replacement therapy, ECMO or death. The
following criteria were analyzed: age, sex, race, clinical symptoms, laboratory and
echocardiographic findings. A p value of < 0.05 was considered as significant. Data were analyzed
with R (v 3.6).
RESULTS
Clinical presentation
The survey included 183 pediatric patients with MIS-C at a mean age of 7.0±4.7 years (range 1.2
months – 18 years old). Patients were from United Kingdom (n=56), France (n=52), Spain (n=32),
USA (n=14), Italy (n=8), Sweden (n=6), Pakistan (n=4), Belgium (n=3), Peru (n=2), Germany
(n=1), Russia (n=1), Portugal (n=1), Mexico (n=1) and Chile (n=1). Their characteristics are
summarized in Table 1. The distribution of patients’ baseline variables according to their country
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
of origin was not statistically different except for race. The percentage of Black race patients was
significantly higher in the United Kingdom (52.7%), France (63.4%) and USA (33.3%) (p<0.001).
Those three countries also have higher rates of Black race in their population according to official
government data (UK 14%, France 15%, USA 20.6%). In our cohort, there was predominance of
male sex (59.6%) and black race (30.6%). Obesity was the most frequent comorbidity (48/183,
26.9%). All patients presented with fever and most with gastrointestinal symptoms (63.9%).
SARS-CoV-2 PCR was positive in 43/114 (37.7%) tested patients and SARS-CoV-2 serology was
positive in 95/110 (86.3%) tested. In total, 114/183 (62.3%) had evidence of current or recent
SARS-CoV-2 infection.
Patients presenting with shock (n=78/183, 42.6%) were older (9.2±4.0 vs 3.8±3.6 in KD-like
patients and 5.9±4.6 in incomplete KD-like, years, p<0.001). They were associated with black race
and had a significantly higher rate of gastrointestinal, cardiorespiratory and neurological
symptoms. Such findings also apply to incomplete-KD presentation, although with a lower
percentage. Positive SARS-CoV-2 serology was significantly higher in patients who presented
with shock (65.4% vs 14.8% in KD-like patients and 51.3% in incomplete KD-like, p<0.001).
Figure 1 and Table 2 illustrate the main clinical characteristics for the 3 types of presentation
(Kawasaki-like, incomplete KD-like and shock) and demonstrate close similarity between
incomplete KD-like and shock presentation.
All patients had NT-Pro-BNP, troponin, d-Dimer, CRP and ferritin levels above normal. However,
patients who presented with shock had significantly lower platelet count and higher NT-Pro-BNP,
d-Dimer, CRP and ferritin. ECG abnormalities were not different among groups. Ischemic
changes, arrhythmia (mainly 1st degree AV block) and abnormal repolarization were the most
common findings.
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Echocardiography at admission was often abnormal (121/183, 66.1%) with dilated coronaries,
pericardial effusion and valvulitis across all types of presentation. Dilated coronaries at admission
were seen in 25.9% of patients with KD-like illness, 27.3% of incomplete KD-like and 12.8% of
those presenting with shock (p=0.06). Shock was associated with significantly higher rate of
pericardial effusion, valvulitis and left ventricular dysfunction on echocardiography.
Hospital course
Treatment
Intravenous immunoglobulin was used in 26/27 (96.2%) KD-like patients and in 137/156 (87.8%)
of the remaining cases; 15/27 (55.6%) KD-like patients and 90/156 (57.7%) of the remaining
patients received steroids. Azithromycin was prescribed in 3/27 (11.1%) KD-like patients and in
11/156 (7.0%) of the remaining MIS-C. Anakinra, infliximab and hydroxychloroquine were
administered in 8, 10 and 5 patients of the total cohort respectively, especially in incomplete KD-
like and shock patients. Aspirin was used in 20/27 (74.1%) KD-like cases and in 104/156 (66.7%)
of the other MIS-C. Anticoagulation with heparin was used in 9/27 (33.3%) KD-like patients and
in 69/156 (44.2%) of the non-KD MIS-C cases.
Outcome of the patients (Table 3)
Overall, 72/183 (39.3%) patients required intravenous inotropic support, 43/183 (23.5%)
mechanical ventilation, and 4/183 (2.2%) ECMO. Three patients died: one 8-month-old male with
typical KD was admitted following 4 days of symptoms. Echocardiography showed preserved left
ventricular function and normal coronary arteries. He was treated with two doses of IVIG and
aspirin but continued to be febrile and was started on steroids and infliximab. On day 11,
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
echocardiography showed dilated right and left coronaries. Clopidogrel and heparin were added to
the treatment. He abruptly deteriorated 2 weeks after admission. He developed giant coronary
aneurysms in all three vessels and experienced fatal cardiac arrest due to massive myocardial
infarction. Another 2-year-old male presented with less than 24 hours of fever, respiratory distress
and shock. Echocardiography revealed severe left ventricular dysfunction with normal coronary
arteries, moderate mitral regurgitation and pericardial effusion. He experienced hemodynamically
significant ventricular arrhythmia. He was put on ECMO and subsequently died following cerebral
injury while on ECMO. The last patient was a 14-month-old girl with a history of tetralogy of
Fallot status post complete repair and invasive ventilation through tracheostomy. She developed
fever, rash, gastrointestinal symptoms, shock and severe left ventricular dysfunction without CAA.
She died following multiple cardiac arrests after 7 days of admission.
Patients with KD-like illness had shorter length of stay than other presentations (7.3±6.4 vs 8.1±6.3
in incomplete KD-like and 9.5±4.3, days, p<0.001) and required overall less intensive care support
when compared to the remaining MIS-C patients. Data is summarized in Table 3.
Following admission, 26/183 patients experienced worse outcome with escalation of care from
ward to PICU and/or need for major treatment (inotropic support, mechanical ventilation, renal
replacement therapy, ECMO) and/or death. Univariate analysis showed that a shorter duration of
symptoms prior to admission was found to be associated with poor patient outcome as measured
by requiring inotropes, mechanical ventilation or ECMO and/or death (bad outcome). There was
an increase of 72.3% risk of worse outcome per everyday reduction (95% CI 0.56-0.90, p=0.006).
Similarly, this shorter duration of symptoms prior to admission was a risk factor for ECMO/death
in the total patient population with a 63.3% increased risk per day reduction (95% CI 0.47-0.82,
p<0.0001).
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
DISCUSSION
We report the largest international series of children with MIS-C after their full hospital course
has been completed. Over 40% of patients with MIS-C presented with shock. They had higher
levels NT-pro-BNP, d-Dimer, CRP and ferritin and developed more cardiac complications other
than CAA, especially pericardial effusion, valvulitis and left ventricular dysfunction. Not
surprisingly, their hospital stay was longer and required more inotropic support and mechanical
ventilation. A minority (nearly 15%) of the MIS-C cases fulfilled criteria for KD. They were
usually stable on admission with less symptoms and less inflammation than other MIS-C cases.
They didn’t experience shock and only had few cardiac complications other than CAA. Their
hospital stay was shorter with less PICU management, inotropic support and mechanical
ventilation, although one of them experienced sudden death in the setting of multiple giant
aneurysms. The remaining MIS-C patients who did not experienced shock predominantly had
fever and inflammation. These patients had a higher rate of CAA but less valvulitis, pericardial
effusion and ventricular dysfunction. They generally had a better outcome.
Other studies have reported clinical characteristics of PIMS-TS/MIS-C cases. Belhadjer et al
described the hospital course and early outcomes of 35 critically sick children with acute heart
failure where ECMO was needed in 28% with favorable outcome in all cases.6 Davies et al reported
a larger cohort of 78 cases of PIMS-TS managed in UK pediatric intensive care units showing that
the indication for ECMO was much less than in the French study.10 In that cohort, male patients
and those from ethnic minority backgrounds were over-represented. Coronary artery abnormalities
were present in 36% of the patients.
Dufort et al described the results of active surveillance for MIS-C in New York State, with 191
cases reported to the state health department of which only 99 met the case definition.8 Up to 80%
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
of them required treatment in the intensive care unit. This percentage differs from our study cohort
where 11% of KD-like patients and 55% of non-KD-like patients required intensive care
admission. It is likely that inclusion criteria in Dufort´s study favored the inclusion of the sickest
patients, whereas our study included a wider spectrum of presentations. Feldstein et al reported
186 MIS-C cases identified by targeted surveillance in 26 U.S states over a 2-month period.9 In
this group, multi organ-involvement was similar to our cohort. Coronary-artery aneurysms were
documented in 8% of children and Kawasaki disease-like features in 40%. Not all patients had
been discharged at the time of publication and therefore is difficult to comment on the outcome.
All these findings are confirmed in our international survey. Additionally, our study is the first to
show that a shorter period of symptoms prior to admission is a risk factor for worse outcome and
for ECMO and/or death.
Previous multicenter reviews from US centers provided a comprehensive description of MIS-C
and clarified its differences with Kawasaki disease, Kawasaki disease shock syndrome and toxic
shock syndrome.10-11 In our study, patients classified as KD-like also had additional uncommon
clinical features for Kawasaki disease such as a higher rate of gastrointestinal symptoms and
frequent association with black race.4,6-11 Moreover, this group of patients showed more
heterogeneous cardiac involvement at presentation than in Kawasaki disease such as ischemic
changes on ECG, left ventricular dysfunction, pericardial effusion and valvulitis on
echocardiography. Finally, this cardiac phenotype was often present within the first days of the
disease as opposed to Kawasaki disease where cardiac features usually occur after 2 or 3 weeks.23-
29 Hence, despite clinical similarities with KD, our results support the concept that these MIS-C
patients belong to a different entity.
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Almost half of the patients fulfilling MIS-C criteria in our series presented with shock. These
patients presented as a fulminant disease with rapidly progressing symptoms requiring immediate
intensive care management and they were associated with ECMO and/or death especially when
time interval between onset of symptoms and admission was short. This type of presentation is
rare in KD. Kawasaki shock syndrome has been typically described in younger patients, after a
long period of symptoms before admission and with a higher rate of coronary artery
abnormalities.30-32
Finally, there were numerous cases who presented with incomplete KD features who did not
experience shock and had little cardiac involvement. The main characteristics of these patients
were fever and inflammation. Their outcome was generally favorable.
Limitations
By means of a survey, we were able to collect the largest available MIS-C dataset rapidly and
worldwide. The symptoms categorized under gastrointestinal, respiratory, cardiovascular and
neurological were not detailed in the data collection. Data collection was kept to a minimum in
order to maximize responses, and this was a drawback to gather management variables such as
doses of drugs. This limited our ability to develop a detailed risk stratification for this cohort of
patients.
Our study is based in the broader UK definition of PIMS-TS and therefore includes critically ill
patients, patients meeting diagnostic criteria for Kawasaki disease and some patients with
unexplained fever and inflammation. Evidence of SARS-CoV-2 infection or exposure is not
mandatory based on such definition whereas CDC and WHO definitions require evidence of such.
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
This requirement might be problematic, since asymptomatic infection are common and antibody
testing is neither universally available nor reliable.
Conclusion
In conclusion, MIS-C has emerged with a wide clinical spectrum at presentation, including KD-
like, life-threatening shock and milder forms with mainly fever and inflammation. The risk for
worse outcome (ECMO and/or death) is associated with a short time-interval between onset-of-
symptoms-and-admission. More studies encompassing larger number of patients are needed to
better describe this new disease, its optimal treatment and long-term monitoring.
Acknowledgments
We thank the following investigators for their support and their participation to the study with
inclusion of patients: Pr Giovanni di Salvo (Universita degli Studi di Padova, Padova, Italy), Pr
Inna I Trunina (Pirogov medical University, Moscow, Russia), Dr Adina Olariu (Southampton
University Hospital, U.K.), Dr Clara Sorribes (Hospital Joan XXIII Tarragona, Spain), Dr Belen
Toral (Hospital 12 de Octubre, Madrid, Spain), Dr Elena Montanes (Hospital 12 de Octubre,
Madrid, Spain), Dr Antonio Martinez (Hospital Regional Universitario, Malaga, Spain), Dr Andre
Rudolph (Pediatric Heart Centre, Stockholm-Uppsala, Sweden), Dr Fatima Pinto (Santa Marta
CHULC, Lisbon, Portugal), Dr Anshoo Dhelaria (Lister Hospital, Stevenage, U.K), Dr Emma
Hulbert-Powell (University Hospitals Plymouth, Plymouth, U.K.), Dr Jens Dubenhorst (St.
Joseph-Krankenhaus, Berlin-Tempelhof Hospital, Berlin, Germany), Dr Roxana Rodriguez
(Universidad Peruana Cayetano Heredia, Lima, Peru), Dr Elmer Zapata Yarleque (Clinica San
Felipe, Lima, Peru), Dr Kimberly Elisabeth McHugh (Medical University of South Carolina,
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Charleston, USA), Dr Shazia Mohsi (Aga Khan University Hospital, Karachi, Pakistan), Dr Ravi
Kumar (Royal Berskhire Hospital, Reading, U.K.), Dr Vikranth Anna Venugopalan
(Sandwell and West Birmingham Hospitals, West Bromwich, U.K), Dr Julio Roberto Erdmenger,
Orellana, Multimedica Norte Hospital, Mexico, Mexico), Dr Mark Daniel Hicar (University at
Buffalo, Buffalo, USA), Dr Nicola Storring, (St George’s Hospital, London, U.K.), Dr Jean
Papadopoulos (Hopital de Jolimont, Brussels, Belgium), Heechan Kang (Royal Brompton
Hospital, London, U.K.), Enrico Piccinelli (Royal Brompton Hospital, London, U.K.)
REFERENCES
1. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory
shock in children during COVID-19 pandemic. Lancet (London, England) 2020; May
23;395(10237):1607-1608
2. DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children
and Young Adults in the Washington, DC Metropolitan Region. The Journal of pediatrics 2020;
May 13. doi: 10.1016/j.jpeds.2020.05.007
3. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID-19 and Kawasaki
Disease: Novel Virus and Novel Case. Hosp Pediatr. 2020; Apr 7;hpeds.2020-0123. doi:
10.1542/hpeds.2020-0123
4. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. Articles An outbreak
of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic : an
observational cohort study. Lancet [Internet]. 2020;6736(20):1–8. Available from:
http://dx.doi.org/10.1016/S0140-6736(20)31103-X
5. Society PIC. PICS Statement: Increased number of reported cases of novel presentation of multi-
system inflammatory disease. https://picsociety.uk/wp-content/uploads/2020/04/PICS-statement-
re-novel-KD-C19-presentation-v2- 27042020.pdf. Accessed on May 18th 2020
6. Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S et al. Acute heart failure in
multisystem inflammatory syndrome in children ( MIS-C ) in the context of global SARS-CoV-2
pandemic. Circulation. 2020; May 17. doi:10.1161/CIRCULATIONAHA.120.048360
7. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of
58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With
SARS-CoV-2. JAMA [Internet]. 2020 Jun 8; Available from:
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
https://doi.org/10.1001/jama.2020.10369
8. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem
Inflammatory Syndrome in Children in New York State. N Engl J Med [Internet]. Available from:
https://doi.org/10.1056/NEJMoa2021756
9. Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem
Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med [Internet]. Available
from: https://doi.org/10.1056/NEJMoa2021680
10. Abrams JY, Godfred-Cato SE, Oster ME, Chow EJ, Koumans EH, Bryant B, et al. Multisystem
Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2: A Systematic
Review. J Pediatr [Internet]. 2020; Available from: https://doi.org/10.1016/j.jpeds.2020.08.003
11. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19–Associated Multisystem Inflammatory
Syndrome in Children — United States, March–July 2020. MMWR Morb Mortal Wkly Rep
2020;69:1074–1080. DOI: http://dx.doi.org/10.15585/mmwr.mm6932e2
12. Davies P, Evans C, Kanthimathinathan HK, Lillie J, Brierley J, Waters G, et al. Intensive care
admissions of children with paediatric inflammatory multisystem syndrome temporally associated
with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. Lancet Child Adolesc
Heal [Internet]. 2020;2(20):1–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32653054
13. Levin M. Childhood Multisystem Inflammatory Syndrome – A new challenge in the Pandemic. N
Engl J Med 2020; 383:393-395. DOI: 10.1056/NEJMe2023158
14. Clark CB, Sanchez-de-Toledo J, Bautista-Rodriguez C, Choueiter N, Lara D, et al. Cardiac
Abnormalities Seen in Pediatric Patients During the SARS‐CoV2 Pandemic: An International
Experience. J Am Heart Assoc [Internet]. 2020 Sep 24;0(0):e018007. Available from:
https://doi.org/10.1161/JAHA.120.018007
15. Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang Z-J. Novel Coronavirus Infection in Hospitalized Infants
Under 1 Year of Age in China. JAMA. 2020 Feb;323(13):1313–4
16. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. N Engl J
Med. 2020; Apr 23;382(17):1663-1665. doi: 10.1056/NEJMc2005073
17. Royal College of Paediatrics and Child Health. Guidance — paediatric multisystem inflammatory
syndrome temporally associated with COVID-19 (https://www.rcpch.ac.uk/resources/guidance-
paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19 )
18. European Centre for Disease Prevention and Control Country Experts. Rapid Risk Assessment:
Paediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children.
2020;(May). (https://www.ecdc.europa.eu/en/publications-data/paediatric-inflammatory-
multisystem-syndrome-and-sars-cov-2-rapid-risk-assessment) Accessed on May 18th 2020
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
19. Network CHA. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with
Coronavirus Disease 2019 (COVID-19). https://emergency.cdc.gov/han/2020/han00432.asp.
Accessed on May 18th 2020
20. World Health Organization. Multisystem inflammatory syndrome in children and adolescents with
COVID-19. . Accessed on May 18th 2020
21. Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, et al. On the Alert for
Cytokine Storm: Immunopathology in COVID-19. Arthritis Rheumatol. 2020; Apr 15. doi:
10.1002/art.41285
22. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider
cytokine storm syndromes and immunosuppression.Lancet 2020; Mar 28;395(10229):1033-1034
23. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis,
treatment, and long-term management of Kawasaki disease: a statement for health professionals
from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on
Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004
Oct;110(17):2747–71
24. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis,
treatment, and long-term management of Kawasaki disease: A scientific statement for health
professionals from the American Heart Association. Circulation. 2017;135:927-999
25. Manlhiot C, Millar K, Golding F, McCrindle BW. Improved classification of coronary artery
abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr Cardiol. 2010
Feb;31(2):242–9
26. McCrindle BW, Li JS, Minich LL, Colan SD, Atz AM, Takahashi M, et al. Coronary artery
involvement in children with Kawasaki disease: risk factors from analysis of serial normalized
measurements. Circulation. 2007 Jul;116(2):174–9
27. Burgner D, Harnden A. Kawasaki disease: what is the epidemiology telling us about the etiology?
Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2005 Jul;9(4):185–94
28. Salo E, Griffiths EP, Farstad T, Schiller B, Nakamura Y, Yashiro M, et al. Incidence of Kawasaki
disease in northern European countries. Pediatr Int. 2012 Dec;54(6):770–2
29. Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J
Epidemiol. 2012;22(2):79–85
30. Gamez-Gonzalez LB, Moribe-Quintero I, Cisneros-Castolo M, Varela-Ortiz J, Muñoz-Ramírez M,
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Garrido-García M, et al. Kawasaki disease shock syndrome: Unique and severe subtype of Kawasaki
disease. Pediatr Int. 2018;60(9):781–90
31. Ma L, Zhang YY, Yu HG. Clinical Manifestations of Kawasaki Disease Shock Syndrome. Clin
Pediatr (Phila) [Internet]. 2018;57(4):428–35. Available from:
https://doi.org/10.1177/0009922817729483
32. Li Y, Zheng Q, Zou L, Wu J, Guo L, Teng L, et al. Kawasaki disease shock syndrome: Clinical
characteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkers for early recognition. Pediatr
Rheumatol. 2019;17(1):1–9
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Table 1. Characteristics of the 183 children with MIS-C
Data are mean (±SD), n (%). Onset/Adm, from onset of symptoms to patient’s admission
Characteristics
Age, years
7.0±4.7
Male
109 (59.6)
Race
Black
Asian
Other
56 (30.6)
22 (12.0)
105 (57.4)
Comorbidities
Obesity
Heart disease
Airway/lung disease
Immunosuppression
Ex-prematurity
48 (26.2)
4 (2.2)
3 (1.6)
2 (1.1)
2 (1.1)
SARS-CoV-2 PCR/serology +
114 (62.3)
Time Onset/Adm, days
5.1 (±3.0)
Duration of admission, days
8.6 (±5.6)
Clinical Features
Fever
124 (100)
Mucocutaneous involvement
120 (65.6)
Gastrointestinal symptoms
117 (63.9)
Conjunctivitis
73 (39.9)
Lymphadenopathy
72 (39.3)
Respiratory symptoms
71 (38.8)
Heart failure (excluding shock)
65 (35.5)
Neurological symptoms
22 (12.0)
Shock at admission
79 (43.2)
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Table 2. Demographics, clinical presentation, electrocardiographic and echocardiographic
comparison between KD-like, incomplete KD-like and shock presentation at admission.
KD-like
n=27 (14.8%)
Incomplete KD-like
n=78 (42.6%)
Shock
n=78 (42.6%)
p value
Age, years
3.8 (±3.6)
5.9 (±4.6)
9.2 (±4.0)
<0.001
Male
19 (70.4)
45 (57.7)
45 (57.7)
0.46
Weight (Kg)
19.8 (±28.0)
26.1 (±16.6)
36.9 (±20.8)
<0.001
Obesity
3 (15.8)
13 (27.7)
14 (23.7)
0.59
Black Race
3 (11.1)
19 (24.7)
34 (43.6)
0.004
Time Onset/Adm, days
5.5 (±3.6)
5.0 (±2.9)
5.0 (±3.0)
0.898
SARS-CoV-2 PCR positive
4 (14.8)
16 (20.5)
23 (29.5)
0.36
SARS-CoV-2 Serology
positive
4 (14.8)
40 (51.3)
51 (65.4)
<0.001
Gastrointestinal symptoms
7 (25.9)
45 (57.7)
65 (83.3)
<0.001
Mucocutaneous
involvement
24 (88.9)
47 (60.3)
49 (62.8)
0.02
Respiratory symptoms
2 (7.4)
28 (35.9)
41 (52.6)
<0.001
Heart failure (excluding
shock)
3 (11.1)
15 (19.2)
47 (60.3)
<0.001
Neurological symptoms
0
3 (3.8)
19 (24.3)
<0.001
Laboratory findings
Platelets, x109 per L
300 (±185)
293 (±201)
207 (±106)
0.02
Lactate (mmol/L)
1.8 (±0.9)
2.1 (±1.6)
3.0 (±2.7)
0.14
NT-Pro-BNP (pg/ml)
2148 (±2593)
7443 (±15975)
17678 (±39609)
<0.001
Troponin (ng/ml)
0.4 (±0.5)
1.0 (±2.0)
1.0 (±1.7)
0.52
d-Dimer (ng/ml)
2699 (±1465)
2334 (±2055)
4594 (±4597)
0.003
CRP (mg/L)
125.5 (±116.0)
150.4 (±111.4)
217.7 (±226.1)
0.004
Ferritin (micrograms/L)
384.5 (±532.8)
394.0 (±364.3)
1131.2 (±1627.1)
<0.001
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
ECG abnormalities at
admission
Ischemia
5 (18.5)
9 (11.7)
14 (17.9)
0.49
Arrythmia
1 (3.7)
4 (5.2)
9 (11.5)
0.23
QTc>500ms
0
1 (1.3)
3 (3.8)
0.39
Abnormal repolarization
1 (3.7)
5 (6.5)
6 (7.7)
0.77
Echocardiography at
admission
Dilated coronaries
7 (25.9)
21 (27.3)
10 (12.8)
0.06
Valvulitis
1 (3.7)
13 (16.9)
25 (32.0)
0.004
Pericardial effusion
4 (14.8)
11 (14.3)
23 (29.5)
0.04
LV dysfunction
4 (14.8)
19 (24.7)
58 (74.4)
<0.001
RV dysfunction
0
1 (1.3)
2 (2.6)
0.63
LVEF (%)
59.6 (±11.6)
58.3 (±10.1)
44.7 (±12.4)
<0.001
Data are mean (±SD), n (%).
Onset/Adm, from onset of symptoms to patient’s admission; BNP, B-type natriuretic peptide; CRP, C-
reactive protein. LV, left ventricle; RV, right ventricle; LVEF, left ventricular ejection fraction
Normal range values: Platelets >150 and <400 x 109 / L; Lactate, normal if < 2 mmol/L; NT-ProBNP 0-
300 pg/ml; Troponin 0-0.4 ng/ml; d-Dimer <250 ng/ml; CRP < 10mg/L; Ferritin 40-400 micrograms/L
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Table 3. Comparison of outcome among patients with KD-like illness vs incomplete KD-like and
shock.
Patients
KD-like
n=27
Incomplete KD-like
n=78
Shock
n=78
p value
Length of stay, days
7.3 (±6.4)
8.1 (±6.3)
9.5 (±4.3)
<0.001
Intensive Care admission
4 (14.8)
20 (25.6)
66 (84.6)
<0.001
Inotropic support
1 (3.7)
5 (6.4)
66 (84.6)
<0.001
Mechanical ventilation
0
9 (11.5)
34 (43.6)
<0.001
Renal replacement therapy
1 (3.7)
0
4 (5.1)
0.3
ECMO
0
1 (1.3)
3 (3.8)
0.32
Death
1 (3.7)
0
2 (2.6)
0.41
Data are mean (±SD), n (%). Extracorporeal membrane oxygenation, ECMO
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
Prepublication Release
©2020 American Academy of Pediatrics
Figure 1. Clinical profiles at presentation for MIS-C patients with KD-like, incomplete KD-like and
shock represented in a radar chart.
Radar chart representing the symptoms for each clinical profile. Each spoke represents one of the variables
and its length is proportional to the magnitude of the percentage of the variable at presentation. A line is
drawn connecting the data values for each spoke related to the same type of clinical profile
0
10
20
30
40
50
60
70
80
90
100
Fever
MucoCutaneous involvement
Lymphadenopathy
Conjunctivitis
Gastrointestinal symptoms
Respiratory symptoms
Cardiovascular symptoms
Neurological symptoms
Clinical profiles at presentation
KD-Like Incomplete KD-like Shock
N=27 (14.7%)
N=78 (42.6%)
N=78 (42.6%)
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
originally published online November 24, 2020; Pediatrics Bonnet and Alain Fraisse
Chowdhury, Ricardo Munoz, Francesco Bianco, Yogen Singh, Michael Levin, Damien
Fanny Bajolle, Paula C Randanne, Diana Salas-Mera, Sandrine Foldvari, Devyani
Carles Bautista-Rodriguez, Joan Sanchez-de-Toledo, Bradley C. Clark, Jethro Herberg,
Multisystem Inflammatory Syndrome in Children: An International Survey
Services
Updated Information &
4554.citation
http://pediatrics.aappublications.org/content/early/2020/11/21/peds.2020-02
including high resolution figures, can be found at:
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or in its
Reprints http://www.aappublications.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
originally published online November 24, 2020; Pediatrics Bonnet and Alain Fraisse
Chowdhury, Ricardo Munoz, Francesco Bianco, Yogen Singh, Michael Levin, Damien
Fanny Bajolle, Paula C Randanne, Diana Salas-Mera, Sandrine Foldvari, Devyani
Carles Bautista-Rodriguez, Joan Sanchez-de-Toledo, Bradley C. Clark, Jethro Herberg,
Multisystem Inflammatory Syndrome in Children: An International Survey
http://pediatrics.aappublications.org/content/early/2020/11/21/peds.2020-024554.citation
the World Wide Web at:
The online version of this article, along with updated information and services, is located on
American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2020 by the
been published continuously since 1948. Pediatrics is owned, published, and trademarked by the
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
by guest on November 27, 2020www.aappublications.org/newsDownloaded from
