ORIGINAL RESEARCH published: 18 January 2021 doi: 10.3389/fped.2020.617039 Prevalence and Clinical Characteristics of SARS-CoV-2 Confirmed and Negative Kawasaki Disease Patients During the Pandemic in Spain Edited by: Elisa Fernández-Cooke 1,2*† , Carlos D. Grasa 3† , Sara Domínguez-Rodríguez 2 , Rolando Cimaz, Ana Barrios Tascón 4 , Judith Sánchez-Manubens 5 , Jordi Anton 5 , Beatriz Mercader 6 , University of Milan, Italy Enrique Villalobos 7 , Marisol Camacho 8 , María Luisa Navarro Gómez 9 , Reviewed by: Manuel Oltra Benavent 10 , Gemma Giralt 11 , Matilde Bustillo 12 , Ana María Bello Naranjo 13 , Sezgin Sahin, Beatriz Rocandio 14 , Moisés Rodríguez-González 15 , Esmeralda Núñez Cuadros 16 , Istanbul University-Cerrahpasa, Turkey Javier Aracil Santos 3 , David Moreno 16 , Cristina Calvo 3 and the KAWA-RACE Study Etienne Merlin, Group ‡ Centre Hospitalier Universitaire de Clermont-Ferrand, France 1 Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain, 2 Pediatric *Correspondence: Research and Clinical Trials Unit (UPIC), Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain, 3 Elisa Fernández-Cooke Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario La Paz, Madrid, Spain, 4 Department of elisafcooke@gmail.com Pediatrics, Hospital Universitario Infanta Sofia, Madrid, Spain, 5 Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Universitat Autònoma de Barcelona, Barcelona, Spain, 6 Department of Pediatrics, Hospital Clínico Universitario Virgen † These authors have contributed de la Arrixaca, Murcia, Spain, 7 Department of Pediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain, 8 Pediatric equally to this work and share first Infectious Diseases, Rheumatology and Immunology Unit, Department of Pediatrics, Hospital Virgen del Rocío, Sevilla, Spain, authorship 9 Department of Pediatrics, Hospital Universitario Gregorio Marañón, Madrid, Spain, 10 Department of Pediatrics, Hospital ‡ KAWA-RACE study group Universitario y Politécnico La Fe, Valencia, Spain, 11 Pediatric Cardiology Unit, Department of Pediatrics, Hospital Universitario collaborative authors are listed at the Vall d’Hebron Barcelona, Barcelona, Spain, 12 Pediatric Infectious Disease Unit, Department of Pediatrics, Hospital end of the article Universitario Miguel Servet, Zaragoza, Spain, 13 Department of Pediatrics, Hospital Universitario Materno-Infantil de Las Palmas de Gran Canaria, Canarias, Spain, 14 Department of Pediatrics, Hospital Universitario de Donostia, Guipuzcoa, Spain, 15 Department of Pediatrics, Hospital Universitario Puerta Del Mar de Cádiz, Cádiz, Spain, 16 Department of Pediatrics, Specialty section: Hospital Regional Universitario de Málaga, Málaga, Spain This article was submitted to Pediatric Rheumatology, a section of the journal Introduction: COVID-19 has a less severe course in children. In April 2020, some Frontiers in Pediatrics children presented with signs of multisystem inflammation with clinical signs overlapping Received: 13 October 2020 Accepted: 25 November 2020 with Kawasaki disease (KD), most of them requiring admission to the pediatric intensive Published: 18 January 2021 care unit (PICU). This study aimed to describe the prevalence and clinical characteristics Citation: of KD SARS-CoV-2 confirmed and negative patients during the pandemic in Spain. Fernández-Cooke E, Grasa CD, Domínguez-Rodríguez S, Barrios Material and Methods: Medical data of KD patients from January 1, 2018 until May Tascón A, Sánchez-Manubens J, 30, 2020 was collected from the KAWA-RACE study group. We compared the KD Anton J, Mercader B, Villalobos E, Camacho M, Navarro Gómez ML, cases diagnosed during the COVID-19 period (March 1–May 30, 2020) that were either Oltra Benavent M, Giralt G, Bustillo M, SARS-CoV-2 confirmed (CoV+) or negative (CoV–) to those from the same period during Bello Naranjo AM, Rocandio B, 2018 and 2019 (PreCoV). Rodríguez-González M, Núñez Cuadros E, Aracil Santos J, Moreno D, Results: One hundred and twenty-four cases were collected. There was a Calvo C and the KAWA-RACE Study Group (2021) Prevalence and Clinical significant increase in cases and PICU admissions in 2020 (P-trend = 0.001 and Characteristics of SARS-CoV-2 0.0004, respectively). CoV+ patients were significantly older (7.5 vs. 2.5 yr) and Confirmed and Negative Kawasaki mainly non-Caucasian (64 vs. 29%), had incomplete KD presentation (73 vs. Disease Patients During the Pandemic in Spain. Front. Pediatr. 8:617039. 32%), lower leucocyte (9.5 vs. 15.5 × 109 ) and platelet count (174 vs. 423 doi: 10.3389/fped.2020.617039 × 109 /L), higher inflammatory markers (C-Reactive Protein 18.5vs. 10.9 mg/dl) Frontiers in Pediatrics | www.frontiersin.org 1 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times and terminal segment of the natriuretic atrial peptide (4,766 vs. 505 pg/ml), less aneurysm development (3.8 vs. 11.1%), and more myocardial dysfunction (30.8 vs. 1.6%) than PreCoV patients. Respiratory symptoms were not increased during the COVID-19 period. Conclusion: The KD CoV+ patients mostly meet pediatric inflammatory multisystem syndrome temporally associated with COVID-19/multisystem inflammatory syndrome in children criteria. Whether this is a novel entity or the same disease on different ends of the spectrum is yet to be clarified. Keywords: Kawasaki disease (KD), children, SARS-CoV-2, COVID-19, shock, multisystem inflammatory syndrome in children (MIS-C), pediatric inflammatory multisystem syndrome (PIMS-TS) INTRODUCTION the Declaration of Helsinki and the ethics committee at Instituto de Investigación Hospital 12 de Octubre approved this study The epidemic of severe acute respiratory syndrome coronavirus (CEIC 15/316). The inclusion of patients with KD was approved 2 (SARS-CoV-2), causing COVID-19, has spread rapidly around following informed consent from parents/guardians. All patient the globe (1). Spain was one of the first European countries to be data were fully anonymized before we accessed them, and then affected after Italy, with the outbreak estimated to have started in the database was reviewed to clean inconsistencies and confirm February 2020. patients’ diagnoses based on information provided. In contrast with adults, the disease in children appears to have a less severe course, with almost no fatalities, and those reported were mainly in children with severe underlining conditions (2, 3). Data Source, Collection, and Management Prospective medical data was included from January 1, 2018 until But in April, some children presented critically ill with fever, May 30, 2020. A research electronic database capture (17) was shock, and signs of multisystem inflammation most of them created and sent to the participant clinicians together with the requiring admission to the pediatric intensive care unit (PICU). study protocol. They presented clinical signs overlapping with Kawasaki disease We established the date of March 1, 2020 as SARS-CoV-2 (KD) (4, 5) triggering alerts to pediatricians. Following the alert, exposed cases, collected cases until May 30, 2020, and considered the World Health Organization (WHO) (6), the European Centre this COVID-19 period (CoV-19p). The patients’ demographic, for Disease Prevention and Control (7), the US Centers for clinical, laboratory, and echocardiographic data were recorded. Disease Control and Prevention (8), and the Royal Collage of Paediatrics and Child Health (9) have all produced definitions for this new entity. It was called pediatric inflammatory Subjects and Case Definitions multisystem syndrome temporally associated with SARS-CoV-2 Individual patient data were reviewed to confirm the diagnosis infection (PIMS-TS) (9) or multisystem inflammatory syndrome of complete or incomplete KD according to the American Heart in children (MIS-C) (8) and case definition and guidance on Association (AHA, 2017) (18). Coronary arteries measurements clinical management was published. followed Z-score of Montreal scale (19), and the classification The cause of KD remains unknown; however, it is suggested according to the Z-score followed AHA guidelines (18); coronary that an infectious agent might trigger the illness (10). A small artery lesions (CAL) were considered if the Z-score > 2, and proportion of KD patients present with Kawasaki disease shock cardiac dysfunction was considered if ejection fraction was <55% syndrome (KDSS) resembling PIMS-TS/MIS-C (11). Cases of (20). All patients <16 years of age diagnosed with KD were KD with concurrent COVID-19 infection were reported (12) included in the study. We looked at the SARS-CoV-2-positive suggesting that SARS-CoV-2 may trigger a cytokine storm patients to see if they fulfilled the WHO definition of MIS-C leading to this newly defined syndrome (13–16). (8) and/or the Royal College of Pediatrics and Child Health This study aimed to compare the prevalence and features of definition of PIMS-TS (9). KD patients before SARS-CoV-2 pandemic and compare them to Two groups were established for comparison. We compared the SARS-CoV-2 positive and negative cases presenting during the KD cases diagnosed during the same period of 2018 and the pandemic. 2019 (PreCoV) to those during CoV-19p that were SARS-CoV-2 negative confirmed by both polymerase chain reaction (PCR) and MATERIALS AND METHODS serology (CoV-) and to those during CoV-19p that were SARS- CoV-2 confirmed with either PCR and/or serology (CoV+). Network Setup To assess the prevalence, we compared the same periods During 2015 a nationwide KD study group named KAWA-RACE of 2018, 2019, and 2020 (March 1, 2020–May 30, 2020). We was setup. Patients were included retrospectively from 2011 excluded patients older than 16 years at the time of diagnosis, through 2016 and prospectively from 2018 onward, based on those patients diagnosed from January 1 to February 29, 2020, declaration from pediatricians of recruiting centers. A total of 93 because the virus could be circulating undetected, but tests were Spanish hospitals joined the network. Our study complies with not routinely performed and patients in whom PCR and serology Frontiers in Pediatrics | www.frontiersin.org 2 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times FIGURE 1 | Trend in Kawasaki disease cases and PICU admissions from 1st March to 30th May during 2018–19 (preCoV-19p) and 2020 (CoV-19p). were not performed. Therefore, we could not assure they were performed, and therefore we could not assure they were SARS- SARS-CoV-2 negative. CoV-2 negative, leaving 109 patients included for further analysis−63 in PreCoV group, 26 CoV+, and 20 CoV–. In the CoV+ group, SARS-CoV-2 PCR was positive in 42% (11/26); Statistical Analysis SARS-CoV-2 serology was positive in 100% (21/21) of patients Baseline characteristics were described through summary that had the test performed, and both were positive in 29% (n = tables reporting frequencies and total records in case of 6). All the patients in the CoV- group had a SARS-CoV-2 PCR categorical variables and median [interquartile range (IQR)] and serology performed that were both negative (Tables 1, 2). when continuous. Chi-squared and Fisher-test (low cell sizes < 5) were applied to assess differences among periods for categorical variables. For continuous variables, the non-parametric U- Mann-Whitney test was applied. Normality was tested with Clinical Characteristics (Table 3) the Shapiro-Wilk test. The incidence was estimated using the The median PreCoV age was 2.55 (IQR, 1.5–3.9), 3.56 (IQR, incidence R package (21), and trend was calculated using the 2.2–6.4) for CoV– and significantly higher 7.54 (IQR, 5.4–10.8) Chi-squared test. R software was used for all analysis (22). for CoV+ patients (p < 001). There was a male predominance PreCoV (62%) and in CoV+ (69%) with a 1:1 ratio in CoV- patients. We found that in PreCoV and CoV– patients, around RESULTS one-fourth of them were non-Caucasian (18/63, 29%, and 5/20, 25%, respectively), while in CoV+ patients this was significantly Nationwide, 124 cases were collected during the periods March higher (16/26, 64%). The median duration of fever was 7 days in 1–May 30, 2018/19/20 with 23 (19%) requiring PICU; the all groups. diagnosis of KD was confirmed for all patients after individual Complete KD was less frequent during the CoV-19p [(CoV– data review. There was a significant increase in cases and PICU 8/20, 40%) and (CoV+ 7/26, 27%) vs. PreCoV (43/63, 68%)]. Of admissions in 2020 (P-trend = 0.001 and 0.0004, respectively) note during the CoV-19p, especially in the CoV+ group, up to (Figure 1). 23% of patients were suspected and treated as KD but did not For comparison with the CoV– and CoV+ groups, we fulfill AHA criteria (complete or incomplete), while during the excluded 15 patients in whom PCR and serology were not PreCoV this did not happen. Patients from CoV-19p who did Frontiers in Pediatrics | www.frontiersin.org 3 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 1 | Microbiological SARS-CoV-2 and blood test results of patients with Kawasaki disease (2018–2019) vs 2020 (CoV+) and (CoV-). 2018–2019 2020 (CoV+) p. value 2020 (CoV-) p. value# N = 63 n = 26 N = 20 Microbiological Results Positive result (non-SARS-CoV-2) 17 (27%) 3 (15%) 0.227 4 (20.0%) 0.659 Coronavirus PCR performed – 26 (100%) 20 (100%) Positive – 11 (42.3%) 0 (0.00%) Coronavirus Serology performed – 21 (80.8%) 20 (100%) Positive – 21 (100%)* 0 (0.00%) PCR+ and Serology+ – 6 (28.6%) 0 (0.00%) Blood tests Hemoglobin (g/dL) 11.6 12.2 (11.0; 0.018 10.9 (10.3; 0.547 (10.6; 12.2) 13.3) 11.9) Leucocytes × 109 /L 15.5 9.50 (7.40; < 0.001 13.8 (8.98; 0.434 (11.9; 20.1) 12.8) 21.7) Platelets at admission 423 (301; 538) 174 (118; 250) < 0.001 294 (232; 423) 0.024 Platelets (min) 371 (284; 446) 174 (118; 250) < 0.001 290 (193; 423) 0.125 Platelets (max) 605 (530; 735) 542 (394; 703) 0.064 599 (299; 711) 0.225 ESR (mm/h) 67.0 46.0 (11.5; 0.010 56.0 (33.2; 0.113 (56.5; 86.5) 61.0) 72.0) C-reactive protein (mg/dl) 10.9 18.5 (11.4; 0.004 14.2 (9.08; 0.450 (6.81; 18.2) 24.2) 16.8) Procalcitonin (ng/mL) 0.85 4.54 (2.56; 0.003 0.48 (0.28; 0.640 (0.39; 2.87) 7.63) 3.33) Albumin (g/L) 3.50 3.40 (3.00; 0.153 3.65 (3.30; 0.779 (3.27; 4.00) 3.80) 3.92) ALT (IU/L) 50.0 24.0 (18.0; 0.061 34.0 (20.0; 0.662 (16.0; 103) 44.0) 69.0) AST (IU/L) 40.0 34.0 (26.0; 0.351 35.0 (23.0; 0.170 (27.0; 60.0) 56.0) 46.0) GGT (IU/L) 42.0 20.5 (15.0; 0.031 15.0 (13.5; 0.137 (20.8; 114) 46.8) 66.8) Nt proBNP 503 (356; 4,766 (3,046; < 0.001 776 (268; 0.849 1,475) 13,596) 1,260) IL_6 185 (75.4; 82.4 (51.7; 310) 84.6) D-dimer 1,883 (671; 2,461 (1,041; 0.591 625 (287; 0.705 3,185) 3,960) 5,478) Fibrinogen 597 (534; 680) 810 (518; 930) 0.289 591 (523; 619) 0.605 Ferritin 185 (128; 247) 476 (358; 966) < 0.001 153 (116; 588) 0.479 # This p-value compares 2018–2019 with 2020 (CoV–). *Not tested in 5 patients. CoV+, SARS-CoV-2 positive patients; CoV–, SARS-CoV-2 negative patients; ESR, Erythrocyte sedimentation rate; ALT, Alanine transaminase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; NT-proBNP, N-terminal pro b-type natriuretic peptide; IL-6, Interleukin 6. not fulfill AHA criteria when treatment was administered, finally Irritability was significantly lower in the CoV+ group. Shock that fulfilled criteria for incomplete KD. was not related to IVIG infusion was observed in an increased Patients CoV+ presented with significantly fewer lips and oral number of patients during the CoV-19p (CoV– 4/20, 20%, and changes than PreCoV patients (85 vs. 50%, p < 0.005). No patient CoV+ 13/26,50%, P < 0.001) vs. 1.6% of patients during the in the CoV+ group had sterile pyuria while it was observed PreCoV. Twenty-three (88.5%) of the CoV+ patients fulfilled in 21% of PreCoV and 35% of CoV– patients. Respiratory both PIMS-TC and MIS-C criteria; from the CoV– cohort, 45% symptoms were not increased during COV-19p, and although of patients fulfilled the criteria for MIS-C, and 40% for PIMS- it was more likely to have an abnormal chest X-ray in the TS, assuming all these patients would have had exposure to CoV+ group, this was not significant. Overall, gastrointestinal SARS-CoV-2 during this period, which is not recorded in the symptoms were observed in 57% PreCoV vs. 65% in CoV+ database (Tables 4A, B). and 55% CoV– with an increased proportion of patients with There were no meaningful differences in blood results abdominal pain in the CoV+ group (33 vs. 58% and 30%). between PreCoV and CoV– patients. Nevertheless, when Frontiers in Pediatrics | www.frontiersin.org 4 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 2 | Detailed microbiological non SARS-CoV-2 results of patients with Kawasaki disease (2018–2019), 2020 (CoV+) and (CoV-). 2018–2019 2020 SARS-COV-2 POSITIVE Patient Microbiology (Non Patient Microbiology (Non PCR Serology SARS-COV-2 (n = 63) SARS-CoV-2) (n = 46) SARS-COV-2) SARS-COV-2 1 (–) 1 (–) (+) Not tested 2 (–) 2 (–) (–) (+) 3 (–) 3 EBV & CMVd (+) Not tested 4 Enterovirusb 4 (–) (+) (+) 5 (–) 5 (–) (+) Not tested 6 (–) 6 (–) (–) (+) 7 Metapneumo & 7 (–) (–) (+) coronavirusa 8 (–) 8 (–) (–) (+) 9 (–) 9 (–) (–) (+) 10 (–) 10 (–) (–) (+) 11 (–) 11 (–) (–) (+) 12 Salmonellac 12 (–) (+) (+) 13 (–) 13 (–) (+) (+) 14 (–) 14 (–) (–) (+) 15 (–) 15 (–) (–) (+) 16 (–) 16 (–) (–) (+) 17 (–) 17 (–) (–) (+) 18 (–) 18 (–) (–) (+) 19 (–) 19 CMV & EBV in blood (+) (+) Not tested 20 (–) 20 (–) (–) (+) 21 (–) 21 Anti-HBc, & anti-HBs (+) (+) Not tested 22 (–) 22 (–) (–) (+) 23 (–) 23 (–) (–) (+) 24 (–) 24 (–) (+) (+) 25 (–) 25 (–) (+) (+) 26 (–) 26 (–) (+) (+) 27 (–) SARS-COV-2 NEGATIVE 28 (–) 27 (–) (–) (–) 29 (–) 28 Mycoplasmad (–) (–) 30 (–) 30 (–) (–) (–) 31 (–) 31 (–) (–) (–) 32 (–) 32 (–) (–) (–) 33 Rhinovirusa 33 (–) (–) (–) 34 (–) 34 Rhinovirus & enterovirusa,b (–) (–) d 35 Parvovirus 35 (–) (–) (–) 36 GASb 36 (–) (–) (–) 37 Rhinovirusa 37 (–) (–) (–) 38 Rhinovirusa 38 Adenovirusa & E.colie (–) (–) 39 Rhinovirusa 39 (–) (–) (–) 40 (–) 40 Bocavirusa (–) (–) 41 (–) 41 (–) (–) (–) 42 (–) 42 (–) (–) (–) 43 (–) 43 (–) (–) (–) 44 (–) 44 (–) (–) (–) (Continued) Frontiers in Pediatrics | www.frontiersin.org 5 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 2 | Continued 2018–2019 2020 Patient Microbiology (Non Patient Microbiology (Non PCR Serology SARS-COV-2 (n = 63) SARS-CoV-2) (n = 46) SARS-COV-2) SARS-COV-2 45 (–) 45 (–) (–) (–) 46 GASb 46 (–) (–) (–) 47 Streptococcus spp.b 47 (–) (–) (–) 48 (–) 49 (–) 50 GASb 51 (–) 52 Parvovirusd 53 (–) 54 Mycoplasmad 55 (–) 56 (–) 57 (–) 58 (–) 59 (–) 60 (–) 61 CMVd 62 Adenovirusa 63 CMVd a Nasopharyngeal aspirate. b Pharyngeal swab. c Stool culture. d Serology (IgM). e Urine culture. (–), Negative; (+), Positive; GAS, Group A Streptococcus; CMV, Cytomegalovirus; EBV, Epstein Barr Virus; Anti-HBc, hepatitis B core antibody; Anti-HBs, hepatitis B surface antibody. All patients from the CoV– group were tested for SARS-COV-2 PCR and serology. comparing PreCoV to CoV+ patients we found in CoV+ group aneurysms were seen. A higher rate of abnormal repolarization significantly lower leucocyte (15.5 × 109 /L vs. 9.5 × 109 /L, p < in electrocardiographic studies was observed in CoV+ patients 0.001) and platelet count (423 × 109 /L vs. 174 × 109 /L, p < 0.001) compared with PreCoV and CoV– patients (19 vs. 3% and and higher terminal segment of the natriuretic atrial peptide 0%, respectively). (NT-proBNP) (503 pg/ml vs. 4,766 pg/ml, p < 0.001), ferritin Treatment with IVIG was given to 95, 100, and 80% of the (185 ng/ml and 476 ng/ml, p < 0.001), C-reactive protein (CRP) PreCoV, CoV–, and CoV+ patients, respectively. The mean days (median, 10.9 vs. 18.5 mg/dl, p < 0.005), and procalcitonin (PCT) of fever onset to IVIG administration were 6 days in all groups. (median, 0.85 vs. 4.54 ng/ml, p < 0.005) (Table 1, Figures 2, 3). A second IVIG dose was given in 14% (8/58), 20% (4/20), and A positive microbiological finding other than SARS-CoV-2 19% (4/21), and corticosteroids were given in 28.6% (18/63), 50% was found in PreCoV, CoV+, and CoV– patients in 27, 15, and (10/20), and 61.5% (16/26), respectively. Only one CoV+ and one 20% of cases, respectively (Table 2). CoV– patient received Tocilizumab, and one patient in the CoV+ group received Anakinra. Outcome and Treatment A significantly higher number of patients were admitted to Echocardiographic examinations were abnormal in PreCoV, PICU from the CoV+ 50% (13/26) vs. the PreCoV group 5% CoV–, and CoV+ patients in 37% (23/67), 45% (9/20), and (3/63), p < 0.001. When comparing the PreCoV to the CoV– 50% (13/26), respectively: CAL were observed in 18/23 (75%), patients, there is still a higher non-significant number of patients 3/9 (33.3%), and 4/13 (39%) among those with abnormal that require PICU 5% (3/63) vs. 30% (6/20). The main reason echocardiography, coronary aneurysms in 7/63 (11%), 2/20 for PICU admission in the CoV+ group was due to cardiac (10%), and 1/26 (3.8%), left ventricular dysfunction in 1/63 dysfunction or shock. Vasoactive support was given to 3/13 (23%) (1.59%), 2/20 (10%), and 8/26 (30.8%), and pericardial effusion in the CoV+ group vs. 1/6 (16%) in the CoV– group and none in 13/23 (56.5%), 4/9 (44.4%), and 3/13 (23.1%). Left ventricular during the PreCoVp. dysfunction was the only echocardiographic finding that was Only one patient from PreCoV had a persistent aneurysm, and significantly higher in CoV+ than PreCoV group (p < 0.001) one in the CoV– is still under follow-up. No deaths were reported and in all cases it was transient. No giant coronary artery (Table 3). Frontiers in Pediatrics | www.frontiersin.org 6 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 3 | Demographics and Clinical Features of patients with Kawasaki disease (2018–2019) vs. 2020 (CoV+) and (CoV–). 2018–2019 2020 (CoV+) p. value 2020 (CoV-) p. value N = 63 n = 26 N = 20 Demographics Male 38 (62.3%) 18 (69.2%) 0.709 10 (50.0%) 0.478 Median age (years) (IQR) 2.55 (1.46; 3.89) 7.54 (5.36; 10.8) <0.001 3.56 (2.20; 6.37) 0.074 Non-Caucasian 18 (28.6%) 16 (64.0%) 0.005 5 (25.0%) 0.981 Clinical features Median days of fever 7.00 (6.00; 8.00) 7.00 (6.00; 9.00) 0.483 7.00 (5.75; 8.00) 0.817 Complete KD 43 (68.3%) 7 (26.9%) <0.001 8 (40.0%) 0.019 Classical criteria Conjunctival injection 49 (77.8%) 22 (84.6%) 0.660 16 (80.0%) 1.000 Lips and oral changes 53 (85.5%) 13 (50.0%) 0.001 16 (80.0%) 0.725 Changes in extremities 41 (66.1%) 8 (32.0%) 0.008 7 (35.0%) 0.028 Polymorphous exanthema 54 (87.1%) 21 (80.8%) 0.515 14 (70.0%) 0.094 Acute lymphadenopathy 32 (50.8%) 11 (42.3%) 0.620 7 (35.0%) 0.329 Other symptoms Respiratory symptoms 40 (63.5%) 19 (73.1%) 0.533 13 (65.0%) 1.000 Rhinorrhea 21 (33.3%) 0 (0.00%) 0.002 2 (10.0%) 0.081 Cough 15 (23.8%) 4 (15.4%) 0.550 3 (15.0%) 0.540 Wheezing 2 (3.17%) 1 (3.85%) 1.000 1 (5.00%) 0.568 Pleural effusion 2 (3.17%) 1 (3.85%) 1.000 0 (0.00%) 1.000 Dyspnea 2 (3.17%) 1 (3.85%) 1.000 0 (0.00%) 1.000 Abnormal Chest-X-ray 6 (17.6%) 10 (38.5%) 0.131 4 (25.0%) 0.707 Musculoskeletal symptoms Arthralgia 8 (12.7%) 1 (3.85%) 0.274 1 (5.00%) 0.680 Arthritis 8 (12.7%) 1 (3.85%) 0.274 1 (5.00%) 0.680 Myalgia 4 (6.35%) 3 (11.5%) 0.412 0 (0.00%) 0.568 Gastrointestinal symptoms 36 (57.1%) 17 (65.4%) 0.629 11 (55.0%) 1.000 Abdominal pain 21 (33.3%) 15 (57.7%) 0.059 6 (30.0%) 0.997 Nausea 4 (6.35%) 3 (11.5%) 0.412 2 (10.0%) 0.628 Vomits 23 (36.5%) 10 (38.5%) 1.000 5 (25.0%) 0.498 Diarrhea 8 (12.7%) 6 (23.1%) 0.336 4 (20.0%) 0.471 Any hepatic alteration 30 (47.6%) 14 (53.8%) 0.763 9 (45.0%) 1.000 Hypertransaminasemia 30 (47.6%) 13 (50.0%) 1.000 8 (40.0%) 0.735 Hyperbilirubinemia 4 (6.35%) 1 (3.85%) 1.000 0 (0.00%) 0.568 Hepatomegaly 4 (6.35%) 2 (7.69%) 1.000 0 (0.00%) 0.568 Cholestasis 1 (1.59%) 1 (3.85%) 0.501 0 (0.00%) 1.000 Nervous system symptoms Headache 6 (9.68%) 3 (11.5%) 0.688 1 (5.26%) 1.000 Irritability 35 (55.6%) 1 (3.85%) <0.001 9 (47.4%) 0.271 Aseptic meningitis 2 (3.17%) 1 (3.85%) 0.328 0 (0.00%) 0.707 Genitourinary symptoms Hematuria 4 (6.35%) 2 (7.69%) 0.680 3 (15.0%) 0.218 Sterile pyuria 13 (21.3%) 0 (0.00%) 0.015 7 (35.0%) 0.427 Shock not related with IVIG 1 (1.59%) 13 (50.0%) <0.001 4 (20.0%) 0.011 PIMS-TS criteria fulfilled – 23 (88.5%) 8 (40%) Complete KD 7/23 (30.4%) 3/8 (37.5%) Incomplete KD 16/23 (69.6%) 5/8 (62.5%) MIS-C criteria fulfilled – 23 (88.5%) 9 (45%) Complete KD 7/23 (%) 2/9 (22.2%) Incomplete KD 16/23 (%) 7/9 (77.8%) Cardiology examinations Any echocardiogram alterations 23 (37.1%) 13 (50.0%) 0.376 9 (45%) 0.594 (Continued) Frontiers in Pediatrics | www.frontiersin.org 7 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 3 | Continued 2018–2019 2020 (CoV+) p. value 2020 (CoV-) p. value N = 63 n = 26 N = 20 Coronary artery lesions 18 (75.0%) 4 (30.8%) 0.023 3 (33.3%) 0.044 Ectasia 12 (19.0%) 3 (11.5%) 0.538 2 (10.0%) 0.500 Aneurysm 7/23 (30.4%) 1/13 (7.7%)* 0.212 2/9 (22.2%) 1.000 7/63 (11.1%) 1/26 (3.85%) 0.429 2/20 (10.0%) 1.000 z score: (small) 7 (100%) 1 (100%) 2 (100%) . Persistent Aneurysm 1/7 (14.3%) 0 (0.00%) 0.250 0 (0.00%) 0.417 Systolic dysfunction Left V. 1/63 (1.59%) 8/26 (30.8%) <0.001 2/20 (10.0%) 0.143 Pericardial effusion 13/23 (56.5%) 3/13 (23.1%) 0.083 4/9 (44.4%) 0.699 Repolarization alterations 2 (3.17%) 5 (19.2%) 0.021 0 (0.00%) 1.000 Pharmacotherapy Days from fever to IVIG 6.00 (5.00; 8.00) 6.00 (4.00; 7.00) 0.194 6.00 (5.00; 8.25) 0.455 IVIG 1st dose 58/63 (92%) 21/26 (80.8%) 0.149 20 (100%) 0.329 IVIG 2nd dose 8/58 (13.8%) 4/21 (19.0%) 0.723 4 (20.0%) 0.492 Corticosteroids 18/63 (28.6%) 16/26 (61.5%) 0.008 10 (50.0%) 0.104 Tocilizumab 0 (0.00%) 1 (33.3%) 1.000 1 (100%) 1.000 Anakinra 0 (0.00%) 1 (14.3%) 1.000 0 – Outcome Admission to PICU 3 (4.92%) 13 (50.0%) <0.001 6 (30.0%) 0.006 Days in PICU 7.00 (5.50; 7.50) 4.00 (3.00; 5.00) 0.247 4.50 (2.25; 6.75) 0.362 Reason PICU admission Myocarditis 0 (0.00%) 6 (23.1%) <0.001 1 (5.00%) 0.241 Cardiac dysfunction 0 (0.00%) 6 (23.1%) <0.001 0 – Suspicion of Sepsis 2 (3.17%) 1 (3.85%) 1.000 0 (0.00%) 1.000 Hypotension shock 1 (1.59%) 9 (34.6%) <0.001 3 (15.0%) 0.042 Vasoactive drugs: 0 (0.00%) 3 (11.5%) 0.023 1 (5.00%) 0.241 Cardiogenic shock 0 (0.00%) 1 (3.85%) 0.292 0 - Respiratory distress 1 (1.59%) 0 (0.00%) 1.000 0 (0.00%) 1.000 Median (interquartilic range). CoV+, SARS-CoV-2 positive patients; CoV–, SARS-CoV-2 negative patients; IQR, interquartile range; KD, Kawasaki Disease; IVIG, intravenous immunoglobulin; Left V, Left Ventricle; MIS-C, multisystem inflammatory syndrome in children; PICU, pediatric intensive care unit; PIMS-TS, pediatric inflammatory multisystemic syndrome temporary associated with SARS-CoV-2. *This patient received IVIG within the first 10 days after fever onset. DISCUSSION COVID-19 some classical KD remain and must not be considered as PIMS. To our knowledge, this is the first study to compare KD The majority of the KD SARS-CoV-2 confirmed cases cases prospectively recruited presenting before and during the fulfilled the PIMS-TC/MIS-C criteria; knowing case definition pandemic and that study separately the SARS-CoV-2 confirmed was intended to be sensitive, and therefore most KD cases positive and negative cases and compare them with pre- are included. Albeit a positive result, detecting SARS-CoV-2 pandemic patients from the preceding years. is suggestive for PIMS-TS/MIS-C, but it is not essential for We report a significant increase in the number of KD diagnosis: a likely contact with patients with COVID-19 is cases in Spain during the SARS-CoV-2 pandemic, with an enough for PIMS-TS, and MIS-C criteria include negative PCR overall 2-fold increase in cases reported as KD in the national for SARS-CoV-2. database and a 10–20-fold increase of cases admitted to PICU Clinical and laboratory features of CoV+ KD patients compared to the previous 2 years. A similar study from northern resemble PIMS-TC/MIS-C and have many significant Italy found a 30-fold increased incidence (13). Despite a 2- differences from PreCoV cases. Patients with CoV+ KD fold increase in the cases reported as KD in the national are older, have non-Caucasian predominance, more intense database when we analyzed each case in this new context, we inflammation, and greater myocardial injury than patients with find that classical KD remains similar, as the prevalence of classical KD. CoV–KD seems not to have increased. Moreover, our series We have compared our data to other European KD series that provides data strongly suggesting that even in the era of also looked at KD and Kawasaki-like cases presenting during the Frontiers in Pediatrics | www.frontiersin.org 8 January 2021 | Volume 8 | Article 617039 Frontiers in Pediatrics | www.frontiersin.org Fernández-Cooke et al. TABLE 4A | Patients from CoV+ cohort, indicating complete/incomplete KD and the criteria met for PIMS-TS and MIS-C diagnosis. Patient number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Complete/Incomplete KD C C I I I C C * * C I C I I * I I I * I I I C I I * Fever > 3 d x x x x x x x x x x x x x x x x x x x x x x x x x x Rash/Conjunctivitis/Mucocutaneous inflammation x x x x x x x x x x x x x x x x x x x x x x x signs Hypotension/Shock x x x x x x x x x x x x x Myocardial dysfunction/pericarditis/valvulitis/CAA x x x x x x x x x x x x x x x x x x x x x Coagulopathy x x x x x x x x x x x x x x GI symptoms x x x # x x # ‡ x x x x x x x x x x x x PCR > 5 mg/dL x x x x x x x x x x x x x x x x x x x x x x x x PCT > 1 ng/mL x x x x x x x x x x x x x x x x x x x No other cause x x x x x x x x x x x x x x x x x x x x x x x x x x PIMS-TS (WHO) Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Persistent fever x x x x x x x x x x x x x x x x x x x x x x x x x x Persistent inflammation x x x x x x x x x x x x x x x x x x x x x x x x x x Single or multi-organ dysfunction x x x x # x x #‡ x x x x x x x x x x x x x x x x x Shock x x x x x x x x x x x x x Cardiac disorder x x x x x x x x x x x x x x x x Respiratory disorder x x x 9 Renal disorder GI disorder x x x # x x #‡ ‡ x x x x x x x x x x x Neurological disorder x x x No other cause x x x x x x x x x x x x x x x x x x x x x x x x x x SARS-CoV-2 + + + + + + + + + + + + + + + + + + + + + + + + + + MIS-C (RCPCH) Yes Yes Yes Yes No Yes Yes No Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes BP, Blood pressure; C, Complete; CAA, Coronary artery abnormalities; GI, Gastrointestinal; I, Incomplete; KD, Kawasaki disease; MIS-C, Multisystem inflammatory syndrome in children; PIMS-TS, Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2; RCPCH, Royal College of Paediatrics and Child Health; WHO, World Health Organization. *These patients didn’t meet the criteria for KD at the moment of admission, but they fulfilled the criteria for incomplete KD during admission. # These patients complained only of mild abdominal pain. ‡ These patients had elevation of liver enzymes but <2 upper limit of normality. January 2021 | Volume 8 | Article 617039 Kawasaki Disease in COVID-19 Times Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 4B | Patients from CoV- cohort indicating complete/incomplete KD and the criteria met for PIMS-TS and MIS-C diagnosis. Patient number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Complete/Incomplete KD I I C C I I C * I I I I C I C I C I C C Fever > 3 d x x x x x x x x x x x x x x x x x x x x Rash/ x x x x x x x x x x x x x x x x x x x Conjunctivitis/Mucocutaneous inflammation signs Hypotension/Shock x x x x Myocardial x x x x x x x x x x x dysfunction/pericarditis/valvulitis/ CAA Coagulopathy x x x x GI symptoms x x x x x x x x x x x PCR> 5 mg/dL x x x x x x x x x x x x x x x x x PCT > 1 ng/mL x x x x x No other cause x x x x x x x x x x x x x x x x x x x x MIS-C (WHO) Yes Yes No No No No No Yes No No No No Yes No Yes Yes Yes Yes No No Persistent fever x x x x x x x x x x x x x x x x x x x x Persistent inflammation x x x x x x x x x x x x x x x x x x x x Single or multi-organ dysfunction x x x x x x x x x x ‡ Shock x x x x Cardiac disorder x x x x x x x x Respiratory disorder x x Renal disorder GI disorder x x x # # x x x x ‡ Neurological disorder No other cause x x x x x x x x x x x x x x x x x x x SARS-CoV-2 - - - - - - - - - - - - - - - - - - - - PIMS-TS (RCPCH) Yes Yes No No Yes No No No Yes No Yes No Yes No Yes Yes No Yes No No BP, Blood pressure; C, Complete; CAA, Coronary artery abnormalities; GI, Gastrointestinal; I, Incomplete; KD, Kawasaki disease; MIS-C, Multisystem inflammatory syndrome in children; PIMS-TS, Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2; RCPCH, Royal College of Paediatrics and Child Health; WHO, World Health Organization. *These patients didn’t meet the criteria for KD at the moment of admission, but they fulfilled the criteria for incomplete KD during admission. # These patients complained only of abdominal pain. ‡ These patients had elevation of liver enzymes but <2 upper limit of normality. Diagnostic criteria of inflammatory: • MIS-C (WHO): ◦ Children and adolescents 0–19 years of age with fever > 3 days AND two of the following: a) Rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, or feet). b) Hypotension or shock. c) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated troponin/NT-proBNP) d) Evidence of coagulopathy (by PT, PTT, elevated D-Dimers). e) Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain). ◦ AND elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin. ◦ AND no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock síndrome. ◦ AND evidence of COVID-19 (RT-PCR, antigen test, or serology positive), or likely contact with patients with COVID-19. • PIMS-TS (RCPCH): ◦ A child presenting with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopaenia) and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal or neurological disorder) with other additional clinical, laboratory or imagining and ECG features. Children fulfilling full or partial criteria for Kawasaki disease may be included. ◦ Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus. ◦ SARS-CoV-2 PCR testing positive or negative. pandemic. Table 5 summarizes data from Pouletty et al. (15), closer in age to those reported in the PIMS-TC series (9 yr) Verdoni et al. (13), and Toubiana et al. (23). (5, 25) and the KD series during the pandemic (7.5–10 yr) The median PreCoV age was 2.55 years that was similar to (13, 15, 26–28). the CoV– group (3.56 yr) and to our retrospective data (24) Historically, KD has known to have male predominance (18), and significantly higher for CoV+ patients (7.54 yr) that was and we found a male predominance in PreCoV and in CoV+ Frontiers in Pediatrics | www.frontiersin.org 10 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times FIGURE 2 | Comparison of laboratory results of Kawasaki disease cases (2018–2019) vs. 2020 (CoV+). Frontiers in Pediatrics | www.frontiersin.org 11 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times FIGURE 3 | Comparison of laboratory results of Kawasaki disease cases (2018–2019) vs. 2020 (CoV–). Frontiers in Pediatrics | www.frontiersin.org 12 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 5 | Summary from Kawasaki disease series during the SARS-CoV-2 pandemic. Fernández-Cooke Fernández-Cooke Pouletty et al. (15)* Verdoni et al. (13)** Toubiana et al. (23)*** et al.* Our Cohort et al.* Our Cohort N = 16 N = 10 N = 21 COVID + N = 26 COVID – N = 20 Median age (years) 7.54 (5.36–10.8) 3.56 (2.2–6.37) 10 (4.7–12.5) 7.5 (3.5) 7.9 (3.7–16.6) Gender-male n (%) 18 (69.2%) 10 (50%) 8 (50%) 7 (70%) 9 (43%) Ethnicity - Caucasian 9 (36%) 15 (75%) 4 (25%)‡ – 12 (29%)‡‡ (n = 42) - Not Caucasian 16 (64%) 5 (25%) – – – Symptoms Fever 26 (100%) 20 (100%) 16 (100%) 10 (100%) 21 (100%) Polymorphous exanthema 21 (80.8%) 14 (70%) 13 (81%) 8 (80%) 16 (76%) Conjunctival injection 22 (84.6%) 16 (80%) 15 (94%) 9 (90%) 17 (81%) Lips and oral changes 13 (50%) 16 (80%) 14 (87%) 7 (70%) 16 (76%) Changes in extremities 8 (32%) 7 (35%) 11 (68%) 5 (50%) 10 (48%) Cervical lymphadenopathy 11 (42.3%) 7 (35%) 6 (37%) 1 (10%) 12 (57%) Complete KD 7 (26.9%) 8 (40%) 10 (62%) 5 (50%) 11 (52%) Gastrointestinal symptoms 17 (65.4%) 11 (55.0%) 13 (81%) 6 (60%) 21 (100%) Respiratory symptoms 19 (73.1%) 13 (65.0%) 2 (12%) – – Neurological symptoms – – 9 (56%) – 12 (57%) Musculoskeletal symptoms – – 1 (6%) 4 (40%) 2 (10%) Imaging Abnormal chest X-ray 10 (38.5%) 4 (25%) 5 (31%) 5 (50%) 8 (44%) (n = 18) Blood tests Hemoglobin (g/dL) 12.2 (11–13.3) 10.9 (10.3–11.9) – 11 (1.2) 8.6 (5.3–12.2) Leucocytes (×109 /L) 9.5 (7.4–12.8) 13.8 (8.98–21.7) 11.5 (9–14.4) 10.8 (6.1) 17.4 (5.4–42.8) Platelets (×109 /L)‡‡ ‡ 174 (118–250) 290 (193–423) 188 (164–244) 130 (32) 499 (78–838) C-Reactive Protein (mg/dL) 18.5 (11.4–24.2) 14.2 (9.08–16.8) 20.7 (16.2–23.6) 25 (15.3) 25.3 (8.9–36.3) Procalcitonin (ng/mL) 4.54 (2.56–7.63) 0.48 (0.28–3.33) – – 22.5 (0.1–448) ESR (mm/h) 46 (11.5–61) 56 (33.2–72) – 72 (24) (n=8) – Albumin (g/dL) 3.4 (3–3.8) 3.65 (3.3–3.92) 2.1 (1.9–2.3) 3.2 (0.3) 2.1 (1.6–3.7) ALT (IU/L) 24 (18–44) 34 (2–69) – 119 (217) 70 (6–257) AST (IU/L) 34 (26–56) 35 (23–46) – 87 (70) – GGT (IU/L) 20.5 (15–46.8) 15 (13.5–66.8) – – 59 (10–205) NT-proBNP (ng/L) 4,766 (3,046–13,596) 776 (268–1,260) BNP ng/L (4,319, 1,255 (929) BNP ng/L (3,354, 2,747–6,493) 16–16,017) (n = 18) D-dimer (mcg/L) 2,461 (1,041–3,960) 625 (287–5,478) – 3,798 (1,318) 4,025 (350–19,330) (n = 20) Interleukin 6 (pg/mL) 185 (75.4–310) 82.4 (51.7–84.6) 270 (136–526) 177.1 (137.4) (n = 4) 170 (4–1,366) (n = 17) Fibrinogen (mg/dL) 810 (518–930) 591 (523–619) – 621 (182) – Ferritin (ng/mL) 476 (358–966) 153 (116–588) 1,067 (272–1,709) 1,176 (1,032) – Microbiological results SARS-CoV-2 PCR + 11 (42.3%) 0 9 (56) 2 (20%) 8 (38%) SARS-CoV-2 serology (IgG 21 (100%) (n = 21) 0 7/8 (87%) 8 (80%) 19 (90%) (n = 20) and/or IgM) + Pharmacotherapy IVIG n (%) 21 (80.8%) 20 (100%) 15 (93%) 10 (100%) 21 (100%) Steroids 16 (61.5%) 10 (50%) 4 (25%) 8 (80%) 10 (48%) Resistance to IVIG 4 (19%) (n = 21) 4 (20%) 10 (62%) 10 (100%) 5 (24%) (persistence of fever >36 h) Cardiology examinations Abnormal echocardiography 13 (50%) 9 (47.4%) 11 (69%) 6 (60%) – Coronary artery dilations 3 (11.5%) 2 (10%) 3 (19%) – 5 (24%) Coronary artery aneurisms 1 (3.85%) 2 (10%) 0 2 (20%) 0 Myocarditis 6 (23.1%) 1 (5%) 7 (43.8%) 5 (50%) § 16 (76%) (Continued) Frontiers in Pediatrics | www.frontiersin.org 13 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times TABLE 5 | Continued Fernández-Cooke Fernández-Cooke Pouletty et al. (15)* Verdoni et al. (13)** Toubiana et al. (23)*** et al.* Our Cohort et al. Our Cohort N = 16 N = 10 N = 21 COVID + N = 26 COVID – N = 20 Pericarditis / pericardial 3 (23.1%) 4 (44.4%) 4 (25%) 4 (40%) 10 (48%) effusion Outcome Admission to PICU 13 (50%) 6 (30%) 7 (44%) – 17 (81%) Shock 13 (50%) 4 (20%) 7 (44%) 5 (50%) 12 (57%) *Median (interquartilic range). **Results as mean (standard deviation). ***Results as median (range). † From Europe, not indicated Caucasian. ‡‡ Parents, not patients, and from Europe, not indicated Caucasian. ‡ ‡ ‡ Corresponding in the different studies to: - Cooke et al. COVID+ Platelets at admission are equal to minimum platelets. - Cooke et al. COVID- Minimum platelets (at admission 294, 193–423). - Pouletty et al. Minimum platelets. - Verdoni et al. not indicated. - Toubiana et al. not indicated. § Indicated ejection fraction < 55%. ALT, Alanine Aminotransferase; AST, Aspatate Aminotransferase; ESR, Erythrosedimentation Rate; GGT, Gamma Glutamyltransferase; IVIG, intravenous immunoglobulin; KD, Kawasaki Disease; NT-proBNP, N-Terminal proB-type Natriuretic Peptide; PICU, Pediatric Intensive Care Unit. patients. African Americans have been affected by the COVID-19 Surprisingly, there is an absence of reported cases of pandemic at a disproportionately higher rate (29). Kawasaki-like MIS associated with SARS-CoV-2 infection in Interestingly, we found a significantly higher proportion of Asian countries where the COVID-19 pandemic started, and non-Caucasians in the CoV+ group, which does not represent where the incidence of KD was the highest. It has been the general Spanish population. Additionally, our retrospective hypothesized that a mutation from a European strain of SARS- study on the same population (2011–2016) found 76% of KD CoV-2 drives a stronger cytokine storm. Serology was more cases had European origin (24). Other studies have also found likely to be positive than PCR in our series, supporting the over-representation of non-Caucasian patients in the KD series postinfectious hypothesis, because the disease appears to occur during the pandemic (5, 15, 23) reaching in a published PIMS- 2–4 weeks after acute SARS-CoV-2 infection or exposure. TC cohort 100% of patients (25), and this may suggest an effect This has also been observed in the patients with PIMS-TC of either social and living conditions or genetic susceptibility (30). and those with heart failure in this context (23, 25–27). The The CoV+ group had more likely incomplete KD than in coronavirus family might represent one of the triggers of KD the PIMS-TS series (5, 23, 31). This phenomenon could be as previously hypothesized (32, 33), and the SARS-CoV-2 spike because PIMS-TC and CoV+ KD are a separate entity or may act as a superantigen driving a cytokine storm that leads to because pediatricians are more aware now and diagnose more hyperinflammation (14, 34). A positive microbiological finding incomplete KD in this context. After conjunctival injection, other than SARS-CoV-2 was found in around 20–25% of the the most frequent classical symptom was erythematous rash PreCoV and CoV– patients. Some of the CoV– negative patients and significantly less common lips and oral changes in CoV+ could have had a different trigger despite the lockdown, but some patients; this was also observed in PIMS-TC patients (5, 23, 31). may have been CoV false negatives explaining why this group No patient in the CoV+ group had sterile pyuria that is typically has overlapping clinical and laboratory features. There were no observed in classical KD patients. meaningful differences in blood results between PreCoV and Respiratory symptoms were not increased in our series, and CoV– patients. Nevertheless, when comparing PreCoV to CoV+ although not significant, it was more likely to have an abnormal patients, we found significantly lower leucocyte and platelet chest X-ray during the pandemic as reported by Toubiana et count and higher NT-proBNP, ferritin, CRP, and PCT in CoV+ al. (23) (44%). Probably the small sample size in our series patients as found in other cohorts (13, 23). These findings are does not allow us to detect significant differences. There was closer to those exhibited by the PIMS-TC/MIS-C and KDSS (35) an increased proportion of patients with abdominal pain in the patients than to classical KD patients. The NT-proBNP levels we CoV+ group, and this symptom was widely observed in PIMS- found were more in line with the Paris Kawa-COVID-19 cohort TC patients (5, 25). Irritability was significantly lower in the (median 4,319 pg/mL) (15) in contrast with Belhadjer et al. that CoV+ group, probably due to the higher median age in this reported 10 times higher levels (mean 41,484 pg/mL) in PIMS-TC group. Shock that was not related to IVIG infusion was observed patients (26). in a significantly increased number of patients who were CoV+. Echocardiographic examinations were abnormal in 50% of This phenomenon was also observed by the other KD pandemic CoV+ patients similar to other KD pandemic series (Table 5) series (Table 5), probably indicating again that these patients are and higher than classical KD cases; this is probably because on the PIMS-TC spectrum. many CoV+ patients presented with left ventricular dysfunction. Frontiers in Pediatrics | www.frontiersin.org 14 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times CAL, defined as Z-score > 2, were observed in a third of In summary, we describe findings in the CoV+ group and our patients presenting during the pandemic, but <10% had remark clinical and laboratory differences to classify them as coronary aneurysms, and this was less likely in the CoV+ PIMS-TC/MIS-C and not classical KD (higher median age, non- group. In PIMS-TC patients, 7–12% present aneurysms (25). Caucasian predisposition, more likely incomplete presentation, Interestingly, there are at least three studies that report no more myocardial dysfunction, less aneurysm development, more coronary aneurysms in Kawa-COVID-19 patients (15) and PICU admission, and higher inflammatory markers). Whether PIMS-TC patients (23, 26); in absolute number, we only had this is a novel entity or the same disease on different ends of the one patient in the CoV+ group with a coronary aneurysm. spectrum is yet to be elucidated. However, SARS-CoV-2 seems Our impression is that the cases associated with SARS-CoV-2, to be a potent trigger that in some patients leads to an aberrant and although they have more cardiac involvement, it is more immune response, especially in older children, and may be due to likely to be left ventricular dysfunction than cardiac aneurysms, previous infections. but this needs to be studied further. It is known that older children with KD and intense inflammation are more likely to present with myocarditis (36). Children with PIMS-TC have been DATA AVAILABILITY STATEMENT described to have mild to moderate heart dysfunction indicating acute myocardial injury and recovering normal cardiac function The raw data supporting the conclusions of this article will be within a week, probably because there is inflammation and made available by the authors, under reasonable request. myocardial oedema but without myocardial necrosis (31, 37). Left ventricular dysfunction was the only echocardiographic finding that was significantly higher in CoV+, and all cases ETHICS STATEMENT were transient. Abnormal repolarization was relatively frequent The studies involving human participants were reviewed and in CoV+ patients in our study; this is probably linked to the approved by Instituto de Investigacion Hospital 12 de Octubre higher proportion of patients with left ventricular dysfunction. approved this study (CEIC 15/316). Written informed consent to A range of ECG abnormalities (14–60%) have been reported in participate in this study was provided by the participants’ legal PIMS-TC patients (5, 25). guardian/next of kin. We found that while 100% of CoV– patients received IVIG, this drops to 80% in the CoV+ patients. We think this is because some may have been treated as PIMS-TC/MIS-C where some clinicians gave steroids directly or they recovered with AUTHOR CONTRIBUTIONS supportive care alone. Although there are no studies yet on EF-C, CG, ABa, JS-M, BM, EV, MC, MN, MO, GG, MB, ABe, the best treatment for this new entity, most groups are giving BR, MR-G, EN, JAr, and DM contributed to the acquisition of first-line treatment with IVIG followed by steroids in some data. EF-C, CG, SD-R, ABa, JS-M, JAn, and CC contributed patients ranging from 33 to 64%, and biological agents in 8– to the analysis and interpretation of the data and drafted the 14% (5, 23, 25, 26). A second IVIG dose was given in a similar manuscript. EF-C, CG, ABa, JS-M, JAn, and CC contributed proportion of patients from all groups, and corticosteroids were to the conception and design of the manuscript. BM, EV, MC, given more frequently in CoV+ patients, probably due to higher MN, MO, GG, MB, ABe, BR, MR-G, EN, JAr, and DM critically inflammation markers and suspicion of PIMS-TC. revised the manuscript. All authors gave final approval and A significantly higher number of patients were admitted to agreed to be accountable for all aspects of work ensuring integrity PICU from the CoV+ group. The reason for PICU admission was and accuracy. due to cardiac dysfunction or shock resembling again PIMS-TC rather than classical KD (5, 23, 25). The mean length of the PICU stay was generally under a week (4–5 days) (23, 25, 27). Only one FUNDING patient from PreCoV had a persistent aneurysm, and one in the CoV- is still under follow-up. No deaths were reported. CG is funded by the Spanish Ministry of Science and Our study has some potential limitations. There is a Innovation—Instituto de Salud Carlos III and Fondos FEDER potential recruitment bias that may have contributed to (Contrato Río Hortega CM19/00015). the high number of patients with Kawasaki-like multisystem inflammatory syndrome, as pediatricians have been more aware due to the alerts. Antibody tests against SARS-CoV-2 were ACKNOWLEDGMENTS performed by different techniques depending on the Hospital; therefore, sensitivity and specificity have a broad range, driving We would like to thank the different Spanish medical pediatric to a potential underdiagnosis. We could not calculate an overall societies that have made the KAWA-RACE network possible: incidence of KD because our network did not achieve total SEIP, SERPE, and SECPCC. We thank members of the KAWA- national coverage. Nevertheless, we think that the number RACE study group for including their patients in this study of patients collected allows us to draw conclusions, and the and SERPE for its support when KAWA-RACE started. In prospective character of our network KAWA-RACE before and memory of Tomisaku Kawasaki (1925–2020) for a life dedicated during the pandemic places us in a privileged setting to have an to describing and understanding this rare disease and taking care overview of what has happened in Spain. of so many Kawasaki disease patients. Frontiers in Pediatrics | www.frontiersin.org 15 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times KAWA-RACE STUDY GROUP Fuente Sánchez (Hospital Universitario Son Espases, Palma de COLLABORATIVE AUTHORS Mallorca), Patricia Aparicio García (Hospital Son Llátzer, Palma de Mallorca), Carlos Briales (Hospital Son Llátzer, Palma de The KAWA-RACE study group is composed by: Mallorca), Joaquín Castilla Crespí (Hospital Son Llátzer, Palma Study coordinator: Elisa Fernández-Cooke (Hospital Doce de de Mallorca), María Elena Colino Gil (Hospital Materno-Infantil Octubre, Spain). de Las Palmas de Gran Canaria), Nerea Delgado Cabrera Scientific committee: Elisa Fernandez-Cooke (Hospital 12 (Hospital Materno-Infantil de Las Palmas de Gran Canaria), de Octubre, Madrid), Cristina Calvo (Hospital Universitario Ana Bello Naranjo (Hospital Materno-Infantil de Las Palmas La Paz, Madrid), Ana Barrios Tascón (Hospital Universitario de Gran Canaria), Jesús Poch Páez (Hospital Materno-Infantil Infanta Sofia, Madrid), Judith Sánchez-Manubens (Hospital Sant de Las Palmas de Gran Canaria), Moneyba García Yáñez Joan de Deu, Barcelona), Jordi Antón (Hospital Sant Joan de (Hospital Materno-Infantil de Las Palmas de Gran Canaria), Deu, Barcelona), Javier Aracil Santos (Hospital Universitario Montse González García (Hospital Universitario Nuestra señora La Paz, Madrid), Esmeralda Nuñez Cuadros (Hospital Regional de Candelaria de Santa Cruz de Tenerife), Maite Viadero Universitario de Malaga), Maria Luisa Navarro Gómez (Hospital (Hospital Universitario Marqués de Valdecilla, Santander), Universitario Gregorio Marañon, Madrid), David Moreno Pérez Beatriz Jiménez Montero (Hospital Universitario Marqués (Hospital Regional Universitario de Málaga), Carlos Grasa de Valdecilla, Santander), Olga Domínguez García (Hospital Lozano (Hospital Universitario La Paz, Madrid). Virgen de la Salud de Toledo), Begoña Losada Pinedo (Hospital Collaborating members: Virgen de la Salud de Toledo), Gema Iñigo Martín (Hospital María Martín Cantero Pérez (Hospital Regional Universitario de Virgen de la Salud de Toledo), Lucía María Escribano Gómez Málaga), Esmeralda Nuñez Cuadros Pérez (Hospital Regional (Hospital General de Albacete), Antonio Cepillo (Hospital Universitario de Málaga), Begoña Carazo Gallego Pérez General de Albacete), Miguel Lillo Lillo (Hospital General de (Hospital Regional Universitario de Málaga), Fernando Sánchez Albacete), María Isabel Buedo (Hospital General de Albacete), García (Hospital La Inmaculada, Almería), Marisol Camacho Laura del Rey (Hospital General de Albacete), Elena Urbaneja Lovillo (Hospital Virgen del Rocío, Sevilla), Renata Marqués Rodríguez (Hospital Clínico Universitario de Valladolid), Sara (Hospital Virgen del Rocío, Sevilla), Olaf Neth (Hospital Rellán Rodríguez (Hospital Clínico Universitario de Valladolid), Virgen del Rocío, Sevilla), Laura, Fernández Silveira (Hospital Teresa Cantero (Hospital de Palencia), Beatriz Plata Izquierdo Virgen del Rocío, Sevilla), Miguel Sánchez Forte (Hospital (Complejo Asistencial Universitario de Salamanca), Luisa Torrecardenas, Almería), Ángeles Ortega Montes (Hospital García-Cuenllas Álvarez (Complejo Asistencial Universitario Torrecardenas, Almería), Leticia Isabel Martínez Campos de Salamanca), Ignacio Oulego Erroz (Hospital de León), (Hospital Torrecardenas, Almería), Beatriz Bravo Mancheño Elena Pérez Santaolalla (Hospital Universitario de Burgos), (Hospital Universitario Virgen de las Nieves, Granada), Carlos Alcalde Martín (Hospital Universitario Río Hortega de Margarita Camacho (Hospital Universitario Virgen de las Nieves, Valladolid), Fernando Centeno Malfaz (Hospital Universitario Granada), Antonio F Medina Claros (Hospital de la Axarquía, Río Hortega de Valladolid), Elena Pérez Gutiérrez (Hospital Murcia), Carlos Salido (Hospital de Jerez), María Torres Rico Universitario Río Hortega de Valladolid), Ma Soledad Jiménez (Hospital Juan Ramón Jiménez de Huelva), Beatriz Ruiz Saez Casso (Hospital General de Segovia), Fredy Prada (Hospital (Hospital Reina Sofia de Córdoba), Elena Fernadez de la Puebla Sant Joan de Déu, Barcelona), Rosa Bou (Hospital Sant Joan Lechuga (Hospital Reina Sofia de Córdoba), Ma José Lirola Cruz de Déu, Barcelona), Estibaliz Iglesias (Hospital Sant Joan de (Instituto Hispalense de pediatría, Sevilla), Kety Maya Carrasco Déu, Barcelona), Joan Calzada (Hospital Sant Joan de Déu, (Instituto Hispalense de pediatría, Sevilla), Moisés Rodríguez Barcelona), Olga Calavia Garsaball (Hospital Joan XXIII González (Hospital Universitario Puerta Del Mar de Cádiz), de Tarragona), Marc Tobeña Rue (Hospital Vall d’Hebron, Enrique Blanca Jover (Complejo Hospitalario Granada), José Barcelona), Gemma Giralt García (Hospital Vall d’Hebron, Uberos Fernández (Complejo Hospitalario Granada), María Barcelona), Zulema Lobato (Xarxa Assistencial i Universitaria Mercedes Ibáñez Alcalde (Hospital de Poniente, Almería), de Manresa), Neus Rius Gordillo (Hospital Sant Joan de Reus), Miguel Lafuente Hidalgo (Hospital Universitario Miguel Servet, Montserrat Pascual Torres (Hospital Sant Joan de Reus), Zaragoza), Lorenzo Jiménez Montañés (Hospital Universitario María Méndez Hernández (Hospital Germans Trias i Pujol de Miguel Servet, Zaragoza), Matilde Bustillo Alonso (Hospital Badalona), Lourdes García (Hospital de Mataró), Sergio Flores Universitario Miguel Servet, Zaragoza), Ariadna Ayerza Casas Villar (Hospital Universitari Mútua de Terrassa), Silvia Yevenes (Hospital Clínico Universitario Lozano Blesa, Zaragoza), Ruiz (Hospital Universitari Mútua de Terrassa), Laura Minguell Bárbara Montes Zapico (Hospital San Agustín, Avilés), Carlos Domingo (Hospital Arnau de Vilanova, Lleida), Anna Ballester Pérez Méndez (Hospital Universitario de Cabueñes, Gijón), (Hospital de Calella), Ana Miralles (Hospital de Palamós), Javier Fernández Aracama (Hospital Universitario Basurto, Berta Pujol Soler (Hospital General de Granollers), Anton Bilbao), Lucía Rodríguez (Hospital Central de Asturias, Oviedo), Foguet Vidal (F. Hospital d’Olot Comarcal de la Garrotxa), María Aleida Ibáñez Fernández (Hospital Central de Asturias, Pere Sala Castellví (Hospital de Barcelona), Angelita Serrano Oviedo), Sandra Navarro Campo (Hospital Central de Asturias, Aguiar (Hospital Comarcal Mòra d’Ebre), José Manuel Siurana Oviedo), Silvia Escribá Bori (Hospital Universitario Son Espases, Rodríguez (Hospital HM Nens. HM Hospitales), Anna Sangorrin Palma de Mallorca), María Concepción Mir Perelló (Hospital Iranzo (Hospital HM Nens. HM Hospitales), Roser Álvarez Pérez Universitario Son Espases, Palma de Mallorca), Ma Ángeles de la (Hospital de la Santa Creu i Sant Pau de Barcelona), Paula Ribes Frontiers in Pediatrics | www.frontiersin.org 16 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times Cajas (Hospital General de Catalunya), Pere Genaró i Jornet Fuenlabrada), Dolores Pérez Campos (Hospital Universitario (Hospital Verge de la Cinta, Tortosa), Ana Grande Tejada de Fuenlabrada), Ma Mercedes Bueno (Fundación Hospital (Complejo Hospitalario Universitario Infanta Cristina, Badajoz), de Alcorcón), David Crespo Marcos (Fundación Hospital Cristina Zarallo (Complejo Hospitalario Universitario Infanta de Alcorcón), Enrique Otheo de Tejada Barásoain (Hospital Cristina, Badajoz), Federico Martinón-Torres (Hospital Clínico Ramón y Cajal, Madrid), Walter Alberto Sifuentes Giraldo Universitario de Santiago de Compostela), Irene Rivero Calle (Hospital Ramón y Cajal, Madrid), María Luz Gámir Gámir (Hospital Clínico Universitario de Santiago de Compostela), (Hospital Ramón y Cajal, Madrid), María José Cilleruelo Antonio Justicia Grande, (Hospital Clínico Universitario de Ortega (Hospital Puerta de Hierro, Majadahonda), Agustín Santiago de Compostela), María López Sousa (Hospital Clínico López López (Hospital Puerta de Hierro, Majadahonda), Universitario de Santiago de Compostela), Alejandro Souto Vilas Cristina Sánchez Vaquerizo (Hospital Puerta de Hierro, (Hospital Clínico Universitario de Santiago de Compostela), Majadahonda), Ana Isabel Usano Carrasco (Hospital Puerta Bernardo López Abel (Hospital Clínico Universitario de de Hierro, Majadahonda), Ester Moreno Gómez (Hospital Santiago de Compostela), Elisa de Miguel Esteban (Hospital San Rafael, Madrid), Olga Carvajal del Castillo (Hospital San Pedro, Logroño), Bibiana Riaño Méndez (Hospital San Rey Juan Carlos, Móstoles), Beatriz Del Pozo Menéndez Pedro, Logroño), Daniel Blázquez (Hospital Universitario Hospital de Torrejón), Katie Badillo Navarro (Hospital de Doce de Octubre, Madrid), Pablo Rojo Conejo (Hospital Torrejón), Fernando Baquero (Hospital Universitario La Paz, Universitario Doce de Octubre, Madrid), Belén Toral (Hospital Madrid), Lucía Deiros Bronte (Hospital Universitario La Paz, Universitario Doce de Octubre, Madrid), Leticia Albert De Madrid), Pablo Fernández Fraga (Hospital Universitario La la Torre (Hospital Universitario Doce de Octubre, Madrid), Paz, Madrid), Nieves Domínguez (Hospital Universitario Jaime de Inocencio (Hospital Universitario Doce de Octubre, Infanta Elena, Madrid), Beatriz Mercader Rodríguez (Hospital Madrid), Mar Santos (Hospital Universitario Gregorio Marañon, Clínico Universitario Virgen de la Arrixaca, Murcia), Francisco Madrid), Rafael Díaz-Delgado de la Peña (Hospital Severo Castro García (Hospital Clínico Universitario Virgen de la Ochoa, Leganés), Paz Collado Ramos (Hospital Severo Ochoa, Arrixaca, Murcia), Águeda Herrera Chamorro (Hospital Clínico Leganés), Alfredo Tagarro (Hospital Universitario Infanta Universitario Virgen de la Arrixaca, Murcia), Paula Alcañiz Sofia, Madrid), Teresa Raga (Hospital Universitario Infanta Rodríguez (Hospital Clínico Universitario Virgen de la Arrixaca, Sofia, Madrid), Libertad Latorre (Hospital Universitario Infanta Murcia), Moisés Sorlí García (Hospital Clínico Universitario Sofia, Madrid), Sara Guillén (Hospital de Getafe), Ignacio Virgen de la Arrixaca, Murcia), María Concepción Rex Nicolás Callejas Caballero (Hospital de Getafe), Luis Manuel Prieto (Hospital Universitario Santa Lucía, Cartagena), Elena Vera Tato (Hospital 12 de Octubre), María Fernanda Guzmán Romero (Hospital Universitario Santa Lucía, Cartagena), Monagas (HM Hospitales Madrid), Isabel Jiménez López (HM Patricia Martínez Olorón (Complejo Hospitalario de Navarra), Hospitales Madrid), Sandra Villagrá (HM Hospitales Madrid), Beatriz Rocandio Cilveti (Hospital de Donostia), Amaia Berridi Viviana Arreo (HM Hospitales Madrid), Roi Piñeiro Pérez (Hospital de Donostia), Laura Santos-Díez Vázquez (Hospital (Hospital General de Vilalba), María de la Parte (Hospital de Cruces, Bilbao), Olaia Fernández (Hospital Universitario General de Villalba), Amalia Tamariz-Martes (Hospital Infantil Basurto, Bilbao), Inmaculada Calvo (Hospital Universitario y Universitario Niño Jesús, Madrid), Marta Llorente Romano Politécnico La Fe, Valencia), Belén Fernández Tudela (Hospital (Hospital del Sureste, Madrid), Maria Belén Hernández Rupérez Universitario y Politécnico La Fe, Valencia), Manuel Oltra (Hospital del Sureste, Madrid), Henar Rojo Sombrero (Hospital Benavent (Hospital Universitario y Politécnico La Fe, Valencia), Universitario Príncipe de Asturias, Alcalá de Henares), Estefanía Marta Dapena Archilés (Hospital General de Castellón), García Cerro (Hospital Universitario Príncipe de Asturias, Franciasco Sanchez Ferrer (Hospital Universitario de San Juan Alcalá de Henares), Irene Maté Cano (Hospital del Henares, de Alicante), César Gavilán (Hospital Universitario de San Juan Coslada), Marta Villares Alonso (Hospital de Móstoles), Marta de Alicante), Ignacio Izquierdo Fos (Hospital Universitario de Pilar Osuna Marco (Hospital de Móstoles), Julia Jensen Veron Elche), María Isabel Serrano Robles (Hospital Universitario (Hospital Infanta Cristina, Madrid), Cristina Zarallo Reales de Elche), Yolanda Herranz Sánchez (Hospital Marina Baixa (Hospital Infanta Cristina, Madrid), María Dolores Rodríguez de Alicante), Enrique Villalobos Pinto (Hospital Infantil Mesa (Hospital Infanta Cristina, Madrid), Santiago Rueda Universitario Niño Jesús, Madrid), Daniel Clemente Garulo Esteban (Hospital Clínico San Carlos, Madrid), José Tomás (Hospital Infantil Universitario Niño Jesús, Madrid), Stella Pie Ramos Amador (Hospital Clínico San Carlos, Madrid), Cristina (Hospital Universitari Doctor Josep Trueta, Girona), Manuel González Menchén (Hospital Clínico San Carlos, Madrid), Marrero Calvo (Hospital Nuestra Señora de Sonsoles, Ávila), Ana Belén Jiménez Jiménez (Hospital Universitario Fundación José María Olmos García (Hospital Mare de Déu dels Lliris, Jiménez Díaz, Madrid), Pilar Galán (Hospital Universitario de de Alcoy, Alicante). REFERENCES 2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary 1. Dong E, Du H, Gardner L. An interactive web-based dashboard of a report of 72314 cases from the Chinese Center for Disease to track COVID-19 in real time. Lancet Infect Dis. (2020) Control and Prevention. JAMA. (2020) 323:1239–42. doi: 10.1001/jama.202 20:533–4. doi: 10.1016/S1473-3099(20)30120-1 0.2648 Frontiers in Pediatrics | www.frontiersin.org 17 January 2021 | Volume 8 | Article 617039 Fernández-Cooke et al. Kawasaki Disease in COVID-19 Times 3. Hoang A, Chorath K, Moreira A, Evans M, Burmeister-morton F, Burmeister covid-19 pandemic in Paris, France: prospective observational study. BMJ. F, et al. COVID-19 in 7780 pediatric patients : a systematic review. ECLINM. (2020) 369:m2094. doi: 10.1136/bmj.m2094 (2020) 16:56. doi: 10.1016/j.eclinm.2020.100433 24. Fernandez-Cooke E, Tascón AB, Sánchez-Manubens J, Antón J, 4. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Lozano CDG, Santos JA, et al. Epidemiological and clinical features of Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. Kawasaki disease in Spain over 5 years and risk factors for aneurysm (2020) 395:1607–160. doi: 10.1016/S0140-6736(20)31094-1 development. (2011- 2016): KAWA-RACE study group. PLoS ONE. (2019) 5. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical 14:e0215665. doi: 10.1371/journal.pone.0215665 characteristics of 58 children with a pediatric inflammatory multisystem 25. Ramcharan T, Nolan O, Lai CY, Prabhu N, Krishnamurthy R, Richter AG, syndrome temporally associated with SARS-CoV-2. JAMA. (2020) 324:259– et al. Paediatric inflammatory multisystem syndrome: temporally associated 69. doi: 10.1001/jama.2020.10369 with SARS-CoV-2 (PIMS-TS): cardiac features, management and short-term 6. World Health Organization. Multisystem Inflammatory Syndrome in Children outcomes at a UK Tertiary Paediatric Hospital. Pediatr Cardiol. (2020) and Adolescents With COVID-19. Geneva: World Health Organization (2020) 41:1391–401. doi: 10.1007/s00246-020-02391-2 7. European Centre for Disease Prevention and Control. Paediatric 26. Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et Inflammatory Multisystem Syndrome and SARS-CoV-2 Infection in Children. al. Acute heart failure in multisystem inflammatory syndrome in children Solna: ECDC (2020) (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. (2020) 8. Information for Paediatric Healthcare Providers. (2020) Available online 142:429–36. doi: 10.1161/CIRCULATIONAHA.120.048360 at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html 27. Grimaud M, Starck J, Levy M, Marais C, Chareyre J, Khraiche D, et al. (accessed October 01, 2020). Acute myocarditis and multisystem inflammatory emerging disease following 9. Royal College of Paediatrics and Child Health. Guidance: Paediatric SARS-CoV-2 infection in critically ill children. Ann Intens Care. (2020) Multisystem Inflammatory Syndrome Temporally Associated With COVID-19. 10:69. doi: 10.1186/s13613-020-00690-8 (2020). London: Royal College of Paediatrics and Child Health. 28. Feldstein L, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. 10. Fernández-Cooke E, Barrios Tascón A, Antón-López J, Grasa Lozano CD, Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl Sánchez-Manubens J, Calvo C. Previous or coincident infections with J Med. (2020) 383:334–46. doi: 10.1056/NEJMoa2021680 suspected Kawasaki disease. Should we change our approach? An Pediatr. 29. Yancy CW. COVID-19 and African Americans. JAMA. (2020) 323:1891– (2019) 90:213–8. doi: 10.1016/j.anpede.2018.06.011 2. doi: 10.1001/jama.2020.6548 11. Kanegaye JT, Wilder MS, Molkara D, Frazer JR, Pancheri J, Tremoulet AH, 30. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics. (2009) OpenSAFELY: factors associated with COVID-19 death in 17 million patients. 123:e783–9. doi: 10.1542/peds.2008-1871 Nature. (2020) 584:430–6. doi: 10.1038/s41586-020-2521-4 12. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID- 31. Wolfler A, Mannarino S, Giacomet V, Camporesi A, Zuccotti 19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. (2020) G. Acute myocardial injury: a novel clinical pattern in children 10:537–40. doi: 10.1542/hpeds.2020-0123 with COVID-19. Lancet Child Adolesc Health. (2020) 4642:1016– 13. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et 7. doi: 10.1016/S2352-4642(20)30168-1 al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of 32. Esper F, Shapiro ED, Weibel C, Ferguson D, Landry ML, Kahn JS. Association the SARS-CoV-2 epidemic: an observational cohort study. Lancet. (2020) between a novel human coronavirus and Kawasaki disease. J Infect Dis. (2005) 6736:1–8. doi: 10.1016/S0140-6736(20)31103-X 191:499–502. doi: 10.1086/428291 14. Henry BM, Green MS, Han H, Luo Q, Mo F, Long L, et al. COVID-19: 33. Shirato K, Imada Y, Kawase M, Nakagaki K, Matsuyama S, Taguchi F. consider cytokine storm syndromes and immunosuppression. Lancet. (2020) Possible involvement of infection with human coronavirus 229E, but not 395:1033–4. doi: 10.1016/S0140-6736(20)30628-0 NL63, in Kawasaki disease. J Med Virol. (2014) 86:2146–53. doi: 10.1002/jmv. 15. Pouletty M, Borocco C, Ouldali N, Caseris M, Basmaci R, Lachaume N, et 23950 al. Paediatric multisystem inflammatory syndrome temporally associated with 34. Cheng MH, Zhang S, Porritt RA, Arditi M, Bahar I. An insertion SARS- CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre unique to SARS-CoV-2 exhibits superantigenic character strengthened cohort. Ann Rheum Dis. (2020) doi: 10.1136/annrheumdis-2020-218814 by recent mutations. bioRxiv. (2020) 1:1–6. doi: 10.1101/2020.05.21.1 16. Buonsenso D, Riitano F, Valentini P. Pediatric inflammatory multisystem 09272 syndrome temporally related with SARS-CoV-2: immunological similarities 35. Gamez-Gonzalez LB, Moribe-Quintero I, Cisneros-Castolo M, Varela-Ortiz with acute rheumatic fever and toxic shock syndrome. Front Pediatr. (2020) J, Muñoz-Ramírez M, Garrido-García M, et al. Kawasaki disease shock 8:574. doi: 10.3389/fped.2020.00574 syndrome: unique and severe subtype of Kawasaki disease. Pediatr Int. (2018) 17. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research 60:781–90. doi: 10.1111/ped.13614 electronic data capture (REDCap)-A metadata-driven methodology and 36. Yoshikawa H, Nomura Y, Masuda K, Hazeki D, Yotsumoto K, Arata M, et al. workflow process for providing translational research informatics support. J Four cases of Kawasaki syndrome complicated with myocarditis. Circ J. (2006) Biomed Inform. (2009) 42:377–81. doi: 10.1016/j.jbi.20008.010 70:202–5. doi: 10.1253/circj.70.202 18. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, 37. Harada M, Yokouchi Y, Oharaseki T, Matsui K, Tobayama H, Gewitz M, et al. Diagnosis, treatment, and long-term management Tanaka N, et al. Histopathological characteristics of myocarditis of Kawasaki disease: a scientific statement for health professionals in acute-phase Kawasaki disease. Histopathology. (2012) 61:1156– from the American Heart Association. Circulation. (2017) 135:e927– 67. doi: 10.1111/j.1365-2559.2012.04332.x 99. doi: 10.1161/CIR.0000000000000484 19. Dallaire F, Dahdah N. New equations and a critical appraisal of coronary Conflict of Interest: The authors declare that the research was conducted in the artery Z scores in healthy children. J Am Soc Echocardiogr. (2011) 24:60– absence of any commercial or financial relationships that could be construed as a 74. doi: 10.1016/j.echo.2010.10.004 potential conflict of interest. 20. Margossian R, Schwartz ML, Prakash A, Wruck L, Colan SD, Atz AM, et al. Comparison of echocardiographic and cardiac magnetic resonance imaging Copyright © 2021 Fernández-Cooke, Grasa, Domínguez-Rodríguez, Barrios Tascón, measurements of functional single ventricular volumes, mass, and ejection Sánchez-Manubens, Anton, Mercader, Villalobos, Camacho, Navarro Gómez, fraction (from the pediatric heart network fontan cross-sectional study). Am J Oltra Benavent, Giralt, Bustillo, Bello Naranjo, Rocandio, Rodríguez-González, Cardiol. (2009) 104:419–28. doi: 10.1016/j.amjcard.2009.03.058 Núñez Cuadros, Aracil Santos, Moreno, Calvo and the KAWA-RACE Study 21. Kamvar ZN, Cai J, Pulliam JRC, Schumacher J, Jombart T. Epidemic Group. This is an open-access article distributed under the terms of the curves made easy using the R package incidence. F1000Res. (2019) Creative Commons Attribution License (CC BY). The use, distribution or 8:139. doi: 10.12688/f1000research.18002.1 reproduction in other forums is permitted, provided the original author(s) 22. R: A Language and Environment for Statistical Computing. (2008). Vienna: R and the copyright owner(s) are credited and that the original publication in Foundation for Statistical Computing. this journal is cited, in accordance with accepted academic practice. No use, 23. Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. distribution or reproduction is permitted which does not comply with these Kawasaki-like multisystem inflammatory syndrome in children during the terms. Frontiers in Pediatrics | www.frontiersin.org 18 January 2021 | Volume 8 | Article 617039