Comparison of Pediatric Inflammatory Multisystem Syndrome temporarily-associated with SARS-CoV-2 and Kawasaki Disease: Results from a nationwide German registry 2020-2021

doi:10.21203/rs.3.rs-1844164/v1

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Comparison of Pediatric Inflammatory Multisystem Syndrome temporarily-associated with SARS-CoV-2 and Kawasaki Disease: Results from a nationwide German registry 2020-2021

https://doi.org/10.21203/rs.3.rs-1844164/v1

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published 20 Jan, 2023

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The connection between Pediatric Inflammatory Multisystem Syndrome (PIMS) and Kawasaki Disease (KD) is not yet fully understood. Using the same national registry, clinical features and outcome of children hospitalized in Germany, and Innsbruck (Austria) were compared.

Reported to the registry were 395 PIMS and 69 KD hospitalized patients. Patient age in PIMS cases was higher than in KD cases (median 7 [IQR 4–11] vs. 3 [IQR 1–4] years). A majority of both PIMS and KD patients were male and without comorbidities. PIMS patients more frequently presented with organ dysfunction, with the gastrointestinal (80%), cardiovascular (74%), and respiratory (52%) systems being most commonly affected. By contrast, KD patients more often displayed dermatological (99% vs. 68%) and mucosal changes (94% vs. 64%), plus cervical lymph node swelling (51% vs. 34%). Intensive care admission (48% vs. 19%), pulmonary support (32% vs. 10%), and use of inotropes/vasodilators (28% vs. 3%) were higher among PIMS cases. No patients died. Upon patient discharge, potentially irreversible sequelae – mainly cardiovascular – were reported (7% PIMS vs. 12% KD).

Despite differences in age distribution and disease severity, PIMS and KD cases shared many common clinical and prognostic characteristics. This supports the hypothesis that the two entities represent a syndrome continuum.

With its start in December 2019, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has emerged as a global pandemic¹. In contrast to its course in adults, among children and adolescents, Coronavirus Disease-19 (COVID-19) usually is mild and has a low hospitalization rate^2–4. In April 2020, a multisystem inflammatory syndrome associated with SARS-CoV-2 first was observed among children in Europe and North America. The World Health Organization (WHO) named this syndrome Pediatric Multisystem Inflammatory Syndrome Temporarily associated with SARS-CoV-2 (PIMS-TS)⁵. Multisystem Inflammatory Syndrome in Children (MIS-C) is a synonymous term proposed by the Centers of Disease Control⁶.

PIMS, the term we have adopted for use with our survey, is a clinical, heterogenous syndrome that partially overlaps with both Kawasaki Disease (KD) and Toxic Shock Syndrome^7–9. Most comparisons between PIMS and KD have been drawn from historical, rather than from concurrent, cohorts^10,11. As a result, it has been difficult to determine whether PIMS and KD are different diseases or whether they instead may be part and parcel of the same syndrome — with the two on a spectrum ranging from less severe (KD) to more severe (PIMS)^12,13. To address this question, the ability to investigate the emergence of PIMS and KD cases simultaneously and in parallel is critical.

Beginning on March 18, 2020, the German Society for Pediatric Infectious Diseases (DGPI), with the support of several other German professional pediatric societies, has collected nationwide data on children and adolescents hospitalized with PIMS in Germany, as well as in the neighboring city of Innsbruck, Austria. As a comparison group, Kawasaki disease (KD) cases not associated with SARS-CoV-2 were collected through the same survey. With a combined dataset of 395 PIMS and 69 KD cases, we compared detailed information on clinical characteristics, disease course and outcome predictors.

Study population and demographics

Between March 18, 2020 and August, 31, 2021, 154 institutions reported 517 patients to the registry. The first recorded admission was on January 7, 2020. Fifty-three patients (10%) were excluded from the analysis, either because they did not meet the PIMS criteria, or because their dataset was incomplete (Suppl. Table 1). The final dataset included 464 patients. Of these, 395 patients were classified as PIMS (PIMS-all, 85%), 242 patients as PIMS with Kawasaki disease features (PIMS-KD, 52%), 153 patients as PIMS without Kawasaki disease features (PIMS-non-KD, 33%), and 69 as Kawasaki disease without association with SARS-CoV-2 infection (KD, 15%). The ratio of PIMS-all as compared to KD was 5.7:1. In comparison to PIMS-KD, more KD cases were complete (54% [37/69] vs. 33% [79/242]).

The number of PIMS-all patients hospitalized per week (between 0-20 cases) peaked at three timepoints during our study period: first in May 2020, then from December 2020 to February 2021, and then again in May-June 2021 (Figure 1A). PIMS-all cases began to rise 5-7 weeks following a spike of COVID-19 hospitalizations (Figure 1A). When the number of SARS-CoV-2 infections went down, PIMS-all cases also decreased 5-7 weeks later. By contrast, KD cases were more evenly distributed (Figure 1B). Interestingly, however, after May 2021, the number of KD cases reported decreased.

An important difference between PIMS-all and KD cases emerged in connection with patient age. In comparison with KD, PIMS-all patients were significantly older (Table 1, Figure 2). While the median age of PIMS-all was 7 years (IQR 4-11), as compared to 3 years (IQR 1-4) in KD cases, PIMS-KD were younger (median 7 years [IQR 4-10]) than PIMS-non-KD patients (median 9 years [IQR 5-13]). Incidence by age group in PIMS patients was highest among 7- to 15-year-old children. Male patients more commonly were affected by both PIMS and KD than were female patients (1.8:1 ratio in PIMS vs. 1.7:1 ratio in KD; Table 1). In addition, it was more common (p=0.025) for KD patients to be Caucasian than it was for PIMS-all patients (Table 1). By contrast, no difference in ethnicity distribution was observed when comparing PIMS-non-KD and PIMS-KD cases. Preexisting comorbidities, most often respiratory and/or cardiovascular-related, were present in 21-29% of both KD and PIMS cases (Table 1).

Clinical characteristics

Among PIMS-all patients, the most common organ involvements were gastrointestinal (80%), cardiovascular (74%), dermatological (68%) and mucosal membranes (64%) (Table 2). Compared to KD, PIMS-all patients more commonly presented with symptoms relating to the gastrointestinal (including ascites), cardiovascular, respiratory, hematological, neurological and renal organ systems. By contrast, KD patients more commonly presented with dermatological, mucosal membrane (including conjunctivitis) and ear-nose-throat symptoms, along with cervical lymphadenopathy, arthralgias and arthritis. Unlike PIMS-non-KD, PIMS-KD patients more commonly presented with dermatological, mucosal membrane (including conjunctivitis) and ear-nose-throat symptoms, along with cervical lymphadenopathy, vomiting, hepatosplenomegaly and anemia. PIMS-non-KD patients more commonly had tachy-/dyspnea, pneumonia, pediatric acute respiratory distress syndrome (pARDS), thickening of enteric walls, and nephritis. Between PIMS-all and PIMS-KD patients, there were no differences in cardiovascular presentation.

In 38% and 39% of cases, respectively, PIMS-all and KD were correctly diagnosed upon admission (Suppl. Table 2). Among PIMS-all cases, the most important differential diagnoses upon admission were gastroenteritis, fever of unknown origin, sepsis, acute appendicitis and KD. Among KD patients, gastroenteritis and acute appendicitis were less commonly considered as potential differential diagnoses.

Laboratory characteristics

No specific laboratory marker exists for either PIMS or KD. As compared to KD, however, PIMS-all patients had higher values for CRP, ferritin, NT-proBNP, troponin T, and d-dimers (Table 2). By contrast, PIMS-KD showed higher titers for NT-proBNP and d-dimers than did PIMS-non-KD patients.

Treatment

Median length of hospitalization was similar between PIMS-all (10d [IQR 8-12]) and KD cases (8d [IQR 6-12]), without there being any difference between PIMS-non-KD and PIMS-KD patients (Table 3). Over 90% of PIMS-all patients received a PIMS-directed therapy during their hospitalizations. Most commonly, this included immunomodulatory medication (89%), followed by systemic antibiotics (71%), hemostaseological medication (51%), pulmonary support (32%), and inotropes/vasodilators (28%).

Overall, PIMS-all were more severely ill than KD patients, as indicated by a higher rate of ICU admission (48% vs. 19%), longer ICU stays (1 day [IQR 0-5] vs. <0.5 day [IQR 0-<0.5]), pulmonary support (32% vs. 10%), including invasive ventilation (12% and 1%, respectively), and inotropes/vasodilators (28% vs. 3%) (Table 3). Similarly, PIMS-non-KD were more severely affected than were PIMS-KD patients, (longer duration of ICU stay, and higher rates of continuous positive airway pressure (CPAP), ventilation and transfusion). PIMS-KD patients more often received IVIG and acetylsalicylic acid (ASA), and less commonly were prescribed heparin and corticosteroids.

Outcome

Among both PIMS-all and KD patients, the overall outcomes were comparably positive (Table 3). Significantly, no patient died. At discharge, 40% of patients, (both PIMS-all and KD), continued to have symptoms considered reversible by the reporting physician. Sequelae reported — almost exclusively cardiovascular — were present in 7% of PIMS-all and 12% of KD patients. The most common cardiovascular sequelae were cardiac insufficiency (n=3 in PIMS-all vs. n=0 in KD) and coronary artery dilatation or coronary artery aneurysms (CAA) (n=15 in PIMS-all vs. n=5 in KD). PIMS-KD more frequently were affected by coronary artery dilatation or CAA than were PIMS-non-KD patients (n=13 vs. n=2).

Our national registry is one of the largest collections of PIMS cases worldwide. It also is the only dataset collecting data in parallel from both SARS-CoV-2-associated PIMS and non-SARS-CoV-2 KD cases. By contrast, other studies comparing PIMS and KD patients have used historical controls^10,11,16. In our analysis of the PIMS and KD cases in this cohort, clinical and epidemiological similarities, as well as differences, became clear. There were more PIMS-all than KD cases reported to the registry (5.7:1 ratio). Reporting of PIMS-all cases climaxed five to seven weeks following a peak in hospitalized COVID-19 cases (Fig. 1). This pattern is well-known in PIMS and typically occurs two to eight weeks following a COVID-19 surge^12,17,18,19. Beginning in May 2021, the reporting of KD cases to our registry decreased; reporting of KD cases has continued to remain low since then, although the reason for this lower-level reporting is not fully understood. Given that reporting to this national PIMS and KD registry is voluntarily, a reporting bias cannot be excluded. The overall numbers of KD cases reported is lower than that reported in a population-based epidemiological study from Germany in 2011-2012²⁰. During 2011–2012, 315 KD cases were submitted within a 24-months-period²⁰, whereas during an 18-months-period in 2020–2021, only 69 cases were documented in the registry.

The male-to-female ratio among PIMS-all and KD cases was comparable, with a higher number of male cases (1.8:1 vs.1.7:1; Table 1). This also has been reported in other cohorts from other countries^{7–11, 16,18}. In our cohort, only one in four PIMS cases and one in five KD cases had a concomitant disease. No singular comorbidity stood out. By contrast, in the United States, a larger proportion of PIMS cases (38%) had underlying conditions, most commonly obesity and chronic lung disease.¹⁹ Coincidentally, among KD cases in a US cohort, the rate of concomitant diseases was lower than in PIMS cases¹⁶.

In our cohort, PIMS and KD patients displayed several key epidemiological and clinical differences. PIMS-KD cases were more commonly incomplete (67%) than KD cases (46%). Similar findings have not been previously reported. In KD, incomplete cases more commonly affected younger patients — a factor often leading to delays in diagnosis and a poorer cardiac prognosis²¹. PIMS-all patients generally were older than KD patients (median of 7 vs. 3 years); among PIMS-all, PIMS-KD patients were younger than PIMS-non-KD patients (median of 7 vs. 9 years). This PIMS vs. KD age difference has been well-documented in the literature^{7–11, 16,22}.

The clinical presentation of PIMS and KD differed as well. Whereas PIMS-all patients more commonly experienced gastrointestinal (including ascites), cardiovascular, respiratory, renal and neurological symptoms, KD patients more commonly presented with signs and symptoms of cutaneous, mucosal, cervical lymphadenopathy, and ear-nose-throat systems, as well as arthritis and arthralgia. We observed the same preferential organ involvement in PIMS-KD as compared to PIMS-non-KD. Among PIMS-non-KD cases, dyspnea/tachypnea, pneumonia, pARDS on X-ray, thickening of enteric walls on ultrasound and nephritis were symptoms/signs that allowed us to distinguish it from PIMS-KD. By contrast, PIMS-KD cases more commonly presented with vomiting and hepatosplenomegaly, as well as mucocutaneous signs and cervical lymphadenopathy.

Although no single laboratory biomarker specifically allows us to distinguish between PIMS-all and KD, inflammatory markers (such as the acute phase proteins CRP and ferritin), the pro-coagulant d-dimer, and cardiac function markers (such as proBNP and troponin T/I) are elevated in both PIMS and KD^12,23. In our cohort, the serum concentration of these markers was higher in PIMS-all than it was in KD. Surprisingly however, d-dimer and proBNP values were higher in PIMS-KD than in PIMS-non-KD, indicating a higher degree of inflammation.

Overall, PIMS patients displayed more severe symptoms than KD patients. PIMS-all cases were admitted to the ICU more frequently and needed greater pulmonary and circulatory support than did KD patients. PIMS-all patients also more often were treated with steroids and heparin and less often with IVIG alone. PIMS-KD were admitted to the ICU less often and required less CPAP and invasive ventilation than did PIMS-all cases; they were given IVIG and ASA more frequently. What role the addition of corticosteroids to IVIG may play in PIMS or KD is open to debate. To date, no randomized clinical trials have been performed for pediatric PIMS^23,24. In patients with cardiovascular failure and shock, corticosteroid treatment is recommended^22,23. By contrast, in ACR’s 2022 treatment guidelines, they recommend corticosteroid treatment in addition to IVIG for all hospitalized PIMS patients²⁵.

The overall outcome of PIMS and KD is favorable. Most patients in our cohort had completely recovered upon discharge. To date, we have had no reports of patients who died of PIMS-all or KD. Mortality in resource-rich countries is reported to be < 1–2%^19,24,26. Sequelae considered irreversible by the reporting physician at time of patient discharge mainly were related to cardiovascular symptoms (in 7% in PIMS-all vs. 12% in KD). These numbers were similar between PIMS-all and KD. It was only among PIMS-KD patients that the rate of developing CAA at discharge was higher than among PIMS-non-KD cases. CAAs in PIMS are usually small (z-score < 5²⁴) and the prognosis is considered more favorable than in KD^13,23,24. Most of the CAAs have resolved within six months following the acute PIMS phase^27,28. However, fatigue and exercise intolerance were reported among up to 50% of PIMS cases upon six-month-follow-up^18,28. This suggests that a structured follow-up is particularly warranted for PIMS and KD patients. In Germany, the register for acute PIMS cases will be supplemented by a follow-up register designed to collect data that will allow us to better understand the long-term prognosis of PIMS. In addition, we plan to analyze data collected during the fourth COVID-19 wave in late 2021 (one dominated by the Delta variant) and the fifth wave in early 2022 (dominated by the Omicron variant), so as to determine whether these variants have altered the clinical picture of PIMS in Germany.

The particular strength of our data lies in its concomitant compilation of PIMS and KD cases in a nationwide registry. This gives us the ability to compare these two entities for the same time period without needing to employ historic controls. This data previously has not been available. The main limitation of our study lies in its voluntary reporting registry design – an approach that may lead to selection bias. Because, however, a COVID-19 registry collecting data from hospitalized acute COVID-19 cases accurately mirrored data trends shown in the statutory notification system²⁹, we nevertheless are confident that our data is representative of the PIMS epidemiological situation in Germany. PIMS is not a notifiable disease in Germany; therefore, no notification data for it exist as such. Due to the nature of PIMS and its severe symptoms, however, underreporting seems even less likely than it would be for acute hospitalized COVID-19 cases.

Despite differences in age distribution and disease severity, widely-shared clinical characteristics and a similar prognosis suggest that PIMS and KD represent a syndrome continuum based upon hyperinflammation triggered by an infectious agent. Follow-on studies of SARS-CoV-2-induced hyperinflammation will help generating hypotheses regarding the etiology of KD.

In Germany, PIMS and KD cases appear to display more clinical and prognostic similarities than they do differences. This suggests that they represent points on a syndrome continuum rather than separate diseases per se.

On March 18, 2020, a prospective registry for children and adolescents hospitalized with PIMS in German pediatric hospitals was established. The study was approved by the Ethics Committee of the Technische Universität Dresden (BO-EK-110032020) and was assigned clinical trial number DRKS00021506. All methods were performed in accordance with the relevant guidelines and regulations. The need for informed consent was waived by the institutional review board of the Ethics Committee of the Technische Universität Dresden (BO-EK-110032020).

Patients And Setting

All German pediatric hospitals were invited to participate by prospectively reporting PIMS and KD cases. For each patient, an electronic case report form was completed in a secure database, with the link accessible through the DGPI website (https://dgpi.de/pims-survey-anleitung/). Included were patients under 20 years old who had been hospitalized with PIMS/KD during the period March 18, 2020 - August 31, 2021. Data collected included demographic characteristics, comorbidities, initial symptoms and clinical signs, laboratory and imaging tests, treatments, disease course during hospitalization, and outcome at hospital discharge. All PIMS and KD cases reported were reviewed by two of the study’s authors (J.A., M.H.) in order to verify whether the cases fulfilled the WHO criteria for PIMS⁵ and/or the American Heart Association criteria for KD¹⁴. Whenever potential differences of opinion emerged, additional information was collected from the reporting physician, discussed within the core team (J.A., R.B., M.H.) and subsequently categorized. PIMS cases were required either to have a positive SARS-CoV-2 serology or -PCR, or else be known to have had close contact with a SARS-CoV-2-infected person. KD cases were required to be either SARS-CoV-2 serology-negative or PCR-negative, without a known close contact with SARS-CoV-2 infection. PIMS patients (labeled PIMS-all) were categorized into two groups: 1) PIMS without features of KD (labeled PIMS-non-KD) and 2) PIMS with features of KD (labeled PIMS-KD), if the patient had at least two classical KD features. This differentiation was chosen based on an early report on an Italian PIMS cohort¹⁵ where the authors observed a high rate of intravenous immunoglobulin G (IVIG) resistance in PIMS patients without KD features and therefore suggested that glucocorticoids (in addition to IVIG) may play a role in this PIMS subgroup¹⁵. PIMS-KD and KD patients were additionally divided into the groups “complete KD” (with 4–5 KD features) or “incomplete KD” (with just 2–3 KD features). Information on the following comorbidity groupings was gathered: respiratory, cardiovascular, gastrointestinal, hepatic, renal, neurological/neuromuscular, psychiatric, hematological, oncological, s/p transplant (solid organ or bone marrow), autoimmune and immunodeficiency (including immunosuppressive treatment). The main outcome categories tracked upon patient discharge were: restitutio ad integrum, persistent symptoms (potentially reversible), sequelae at discharge (potentially irreversible), and case fatality.

Statistical Analysis

For statistical analysis, Microsoft Excel v.2010 and the software programs IBM SPSS v.25.0 and R v3.6. were employed.

Based upon the presence or absence of KD features, the following comparisons were conducted: (A) patients with PIMS and Kawasaki (PIMS-KD) vs. patients with PIMS without Kawasaki (PIMS-non-KD); and (B) patients with PIMS (both with and without Kawasaki [PIMS-all]) vs. patients with Kawasaki without SARS-CoV-2 infection (KD).

Sociodemographic characteristics were described by absolute and relative frequencies for categorical variables, while continuous variables were described by median and first/third quartile. Group differences among these variables were tested using Fisher's exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. In addition, group differences were assessed with respect to preliminary diagnoses on admission, comorbidities, symptoms, diagnostic procedures, laboratory findings, therapies and outcomes. Differences regarding the probability of occurrence in the event of binary variables, as well as regarding median values in the event of continuous variables, were estimated. Confidence intervals and p-values were derived by the Wald method for differences in probabilities, as well as by the bootstrap method with 1,000 replications for differences in median values. The significance and confidence levels were set to 0.05 and 0.95, respectively.

ACR American College of Rheumatology

AHA American Heart Association

ASA Acetylsalicylic Acid

CAA Coronary Artery Aneurysm(s)

CDC Centers of Disease Control

CI Confidence Interval

COVID-19 Coronavirus Disease 2019

CPAP Continuous Positive Airway Pressure

CRP C-Reactive Protein

DGPI Deutsche Gesellschaft für Pädiatrische Infektiologie (German
Society for Pediatric Infectious Diseases)

FUO Fever of Unknown Origin

ICU Intensive Care Unit

IQR Interquartile Range

IVIG Immunoglobulin G

KD Kawasaki Disease

MIS-C Multisystem Inflammatory Syndrome in Children

NT-proBNP N-terminal pro Brain Natriuretic Protein

pARDS pediatric Acute Respiratory Distress Syndrome

PCR Polymerase Chain Reaction

PID Primary Immunodeficiency

PIMS Pediatric Inflammatory Multisystem Syndrome

PIMS-KD Pediatric Inflammatory Multisystem Syndrome with Kawasaki
Disease features

PIMS-non-KD Pediatric Inflammatory Multisystem Syndrome without Kawasaki
Disease features

PIMS-TS Pediatric Inflammatory Multisystem Syndrome temporarily-
associated with SARS-CoV-2

SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus type 2

s/p Status post

TSS Toxic Shock Syndrome

vs. versus

WHO World Health Organization

Acknowledgements:

Members of the PIMS-DGPI working group are: Klinik für Kinder- und Jugendmedizin Altenburger Land (K. Ehrentraut), Klinik für Kinder- und Jugendliche St. Marien Amberg (A. Fiedler), Klinik für Kinder- und Jugendmedizin Aschaffenburg-Alzenau (M. Herzog), Klinik für Kinder- und Jugendmedizin Aue (J. Meister), Klinik für Kinder- und Jugendmedizin Augsburg (M. Kuska, U. Walden), Klinik für Kinder- und Jugendliche Josefinum Augsburg (T. Keller, C. Schlick), Klinik für Kinder- und Jugendmedizin Bad Kreuznach (R. Bullmann), Klinik für Kinder- und Jugendmedizin Bad Mergentheim (D. Jantzen), Klinik für Kinder- und Jugendliche Bamberg (L. Hacker), Klinik für Kinder- und Jugendmedizin Berlin-Buch (F. Kelch), Klinik für Kinder- und Jugendmedizin Berlin-Lichtenberg (F. Eißler, S. Spinner, T. Stöhring), Klinik für Kinder- und Jugendmedizin Berlin-Neukölln (S. Akanbi, F. Dejas, S. Endres, A. Höche, J. Grüner, Y. Morawski, I. Östreicher, L. Spath), Klinik für Kinder- und Jugendmedizin Berlin-Westend (I. Glaser, M. Grünwedel, L. Motzkus, D. Sumbadze), Klinik für Kinder- und Jugendmedizin Berlin-Spandau (F. Mader), Klinik für Kinder- und Jugendmedizin Berlin-Tempelhof (F. Menzel, T. Niehaus), Klinik für Pädiatrie, Charité Universitätsmedizin Berlin (B. Opgen-Rhein, H. Ringe), Klinik für Kinder- und Jugendmedizin Bielefeld (T. Boesing, P. Ioannou, E. Sönmez), Klinik für Kinder- und Jugendmedizin Böblingen (S. Weber), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Bochum (F. Brinkmann), Zentrum für Kinderheilkunde, Universitätsklinikum Bonn (A. Weigert), Klinik für Kinder- und Jugendmedizin Bottrop (M. Kuhnigk), Klinik für Kinder- und Jugendmedizin Braunschweig (J.W. Richter), Prof.-Hess Kinderklinik Bremen-Mitte (L. Buchtala, P. Kaiser-Labusch), Klinik für Kinder- und Jugendmedizin Celle (M. Kirschstein), Klinik für Kinder- und Jugendmedizin Chemnitz (U. Höpner), Klinik für Kinder- und Jugendmedizin Chemnitz-Rabenstein (A. Samol), Kinder- und Jugendklinik Coesfeld (D. Willmer), Klinik für Kinder- und Jugendmedizin Cottbus (U. Blümlein), Kinderklinik Darmstadt (C. Baßmann, J. Keck, M.S. Keßner, J. Rambow, J. Tränkner, T. Treichel, A. Werner), Kinder- und Jugendklinik Datteln (M. Mauritz), Klinik für Kinder- und Jugendmedizin Deggendorf (G. Beier), Klinik für Kinder- und Jugendmedizin Detmold (S. Blume), Klinik für Kinder- und Jugendmedizin Dinslaken (K. Döhring, C. Kleff), Klinik für Kinder- und Jugendmedizin Dortmund (H. Kalhoff, L.G. Moise, D. Schneider), Klinik für Kinder- und Jugendmedizin Dresden (N. Lenz), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Dresden (J. Armann, R. Berner, L. Galow, Y. Zeißig), Kinderklinik Duisburg (M. Degirmenci), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Düsseldorf (M. Kohns Vasconcelos), Klinik für Kinder- und Jugendliche Düsseldorf (M. Gappa), Klinik für Kinderheilkunde Düsseldorf (D. Lubitz), Klinik für Kinder- und Jugendmedizin Eberswalde (S. Jenssen), Klinikum Eichsfeld (M. Himpel), Klinik für Kinder- und Jugendmedizin Erfurt (B. Müller, K. Sauerbrey), Klinik für Kinder- und Jugendmedizin Essen (F. Pentek), Klinik für Kinderheilkunde Universitätsklinikum Essen (D. Bernard, S.C. Goretzki, K. Holtkamp, M. Schäfer), Klinik für Kinder- und Jugendliche Esslingen (A. Berger, B. Brenner), Kinderhospital Frankfurt (R. Kitz), Klinik für Kinder- und Jugendmedizin Frankfurt-Höchst (L. Schrod), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Frankfurt (H. Donath, R. Kosteczka, M. Merker, R. Schrewe), Klinik für Kinder- und Jugendmedizin Freiberg (A. Markowsky, U. Zügge), Zentrum für Kinder- und Jugendmedizin Universitätsklinikum Freiburg (K. Fingerhut, M. Hufnagel), Klinik für Kinder- und Jugendmedizin RKK-Klinikum Freiburg (J. Budde), Klinikum Freising (N. Schaeffer), Klinik für Kinder- und Jugendmedizin Freudenstadt (J. Brühler), Fachabteilung für Kinder- und Jugendmedizin Garmisch-Partenkirchen (L. Schulteß), Kinder- und Jugendklinik Gelsenkirchen (G. Lautner, L. Lindemann), Klinik für Kinder- und Jugendmedizin Gelsenkirchen (H. Libuschewski, S. Seidel), Waldklinikum Gera (L. Hempel), Kinderklinik Gummersbach (C. Hittmeyer, V. Iliaev), Kinderklinik Hagen (K-A. Hilker, M. Horstkemper, I. Schumacher), Pädiatrie Universitätsklinikum Halle (K. Parthey, S. Trau, A-S. Yussif), Kinderkrankenhaus Hamburg-Altona (M. Dittrich, C. Heinrich, S. Kowski), Kinder- und Jugendmedizin Hamburg Mariahilf-Klinik (C. Schmitt, F. Wehrhoff), Kinderkrankenhaus Hamburg-Wilhemstift (A. Eißner, A-K. Steiner, T. Wahjudi, S. Wenzel), Kinder- und Jugendkrankenhaus Hannover (S. Arens), Klinik für Pädiatrie Universitätsklinikum Hannover (J. Ohlendorf, K. Schütz), Klinik für Kinder- und Jugendmedizin Herford (I. Malath), Kinderzentrum Hildesheim (A. Diederichs), Klinik für Allgemeine Pädiatrie und Neonatologie Universitätsklinikum Homburg (A. Simon), Klinik für Kinder- und Jugendheilkunde Universitätsklinikum Innsbruck (J. Brunner), Klinik für Kinder- und Jugendmedizin Itzehoe (G. Hillebrand), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Jena (C. Richter), Klinik für Kinder- und Jugendmedizin Kaiserslautern (G. Koukli), Klinik für Kinder- und Jugendmedizin Karlsruhe (S. Aggar, A. Finster, E. Spancken, L. Thiel), Klinik für Kinder- und Jugendmedizin Kassel (B. Stastny), Pädiatrie Klinikum Kaufbeuren (G. Wehl), Klinik für Kinder- und Jugendmedizin Kiel (N. Lorenzen), Klinik für Kinder- und Jugendmedizin Koblenz (T. Hoppen), Kinder- und Jugendmedizin Uniklinik Köln (A. Oberthür), Kinderklinik Köln-Porz (J. Horstmann, C. Ponsa), Klinik für Kinder- und Jugendmedizin Köln (K. Böckenholt), Klinik für Kinder- und Jugendmedizin Konstanz (K. Waldecker), Klinik für Kinder- und Jugendmedizin Krefeld (A. Reil), Klinik für Kinder- und Jugendheilkunde Landau (M. Höfgen), Klinik für Kinder- und Jugendmedizin Landsberg (A. Schnellke, M. Steidl), Klinik für Kinder- und Jugendmedizin Lepizig-St. Georg (K. Anders), Klinik für Kinder- und Jugendmedizin Lichtenstein (F. Ebert), Klinik für Kinder- und Jugendmedizin Limburg (D. Fischer), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Lübeck (R. Bonacker, M. Müller), Klinik für Kinder- und Jugendliche Lüdenscheid (H. Frenzke), Klinik für Kinder- und Jugendmedizin Ludwigshafen (M. Carré-Schoppe), Klinik für Kinder- und Jugendmedizin Lüneburg (M. Aderhold), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Marburg (S. Foth), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Minden (G. Cvetanovic, S. Haag), Klinik für Kinder- und Jugendliche Mönchengladbach (D. Kever, O. Schroers), Haunersche Kinderklinik München (A. Czwienzek, S. Kwaschnowitz), Klinik für Kinder- und Jugendmedizin München-Nymphenburg (M-M. Borchers), Klinik und Poliklinik für Kinder- und Jugendmedizin Universitätsklinikum Müchen-Schwabing (N. Rieber), Klinik für Kinderkardiologie- und Pädiatrische Intensivmedizin Klinikum der Universität München (M. Hermann, A. Jakob), Klinik für Kinder- und Jugendmedizin St. Franziskus-Hospital Münster (K. Knop), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Münster (A. van den Heuvel), Klinik für Kinder- und Jugendmedizin Neuburg (N. Halwas, F. Wild), Klinik für Kinder- und Jugendliche Neuss (C. Mampe), Klinik für Kinderheilkunde und Jugendmedizin Neustadt am Rübenberge (A. Teichmann), Klinik für Kinder- und Jugendmedizin Neuwied (J. Meyer), Cnopf’sche Kinderklinik Nürnberg (M. Scheffler, F. Wolf), Klinik für Kinder- und Jugendliche Oberhausen (A. Stockmann), Klinik für Kinder- und Jugendmedizin Offenbach (M. Engler), Klinik für Kinderheilkunde und Jugendmedizin Offenburg (F. Konrad, T. Reinhardt), Zentrum für Kinder- und Jugendmedizin Oldenburg (H. Köster), Zentrum für Kinder- und Jugendmedizin Osnabrück (M. Menden), Kinderklinik Passau (B. Steif), Klinik für Kinder- und Jugendmedizin Pforzheim (B. Demirdelen), Klinik für Kinder- und Jugendmedizin Plauen (S. Pötzsch), Kinder- und Jugendklinik Potsdam (L. Meyer-Dobkowitz), Klinik für Kinder- und Jugendliche Ravensburg (C. Bölke), Klinik und Poliklinik für Kinder- und Jugendmedizin Universitätsklinikum Regensburg (S. Gerling), Klinik für Kinder- und Jugendmedizin Reutlingen (H.-C. Schneider), Klinik für Kinder- und Jugendmedizin Rodewisch (G. Adamiak-Brych), Klinik für Kinder- und Jugendmedizin Rosenheim (A. Kirchner), Kinder- und Jugendklinik Universitätsklinikum Rostock (B. Wichmann), Klinik für Kinder- und Jugendliche Rotenburg (C. Kluthe), Klinik für Kinder- und Jugendmedizin Rüsselsheim (M. Berwald), Klinik für Kinder- und Jugendmedizin Saarbrücken (C. Jung, D. Wurm), Klinik für Kinder- und Jugendmedizin Salzgitter (C. Weste), Klinik für Kinder- und Jugendmedizin St. Augustin (S. Kelzon), Klinik für Kinder- und Jugendliche Schwäbisch-Hall (C. Hanke), Klinik für Kinder- und Jugendliche Schweinfurt (O.-J. Bayrhof, A. Eff), Klinik für Kinder- und Jugendmedizin Schwelm (M.-A. Ahmed), Klinik für Kinder- und Jugendliche Singen (D. Klauwer, A. Trotter), Klinik für Kinder- und Jugendliche Solingen (V. Soditt), Klinik für Kinder- und Jugendmedizin Speyer (J. Heinrich, M. Mohorovicic), Klinik für Kinder- und Jugendmedizin Stade (K. Vehse, L. Warneke), Klinik für Kinder- und Jugendmedizin Stollberg (N. Ido, A. Rühlmann), Zentrum für Kinder- und Jugendmedizin Stuttgart-Olgaspital (A. Hospach, F. Reichert), linik für Kinder- und Jugendmedizin Suhl (K. Goj), Klinik für Kinder- und Jugendmedizin Trier (S. Gitzinger), Universitätsklinik für Kinder- und Jugendmedizin Tübingen (J. Kern), Klinik für Kinder- und Jugendmedizin Universitätsklinikum Ulm (L. Baumbach), Klinik für Kinder- und Jugendmedizin Velbert (N. Wrenger), Klinik für Kinderheilkunde und Jugendmedizin und Kinderchirurgie Villingen-Schwenningen (T. Groteclaes), Zentrum für Kinder- und Jugendliche Wesel (S. Flümann), Klinik für Kinder- und Jugendmedizin Wiesbaden (C. Fremery, H. Machata, G. Müller, L. Vischer), Klinik für Kinder- und Jugendmedizin Winnenden (M. Müller, V. Lange), Kinder- und Jugendklinik Witten (J. Knechtel), Klinik für Kinder- und Jugendmedizin Wittlich (F. Olar), Klinik für Kinder- und Jugendmedizin Wolfsburg (A. Biering), Klinik für Kinder- und Jugendmedizin Worms (F. Sternberg), Kinder- und Poliklinik Universitätsklinikum Würzburg (J. Liese), Klinik für Kinder- und Jugendmedizin Wurzen (K. Gröger), Klinik für Kinder- und Jugendmedizin Zittau (H. Reck), Klinik für Kinder- und Jugendmedizin Zwickau (A. Haupt).

Contributors’ Statement Page

MH, JA, AH, and RB designed the registry.

MH, JA MD, and ND managed the database and validated the data.

DTS, AT, and RB coordinated resources.

MH, JA, MR, and JS analyzed the registry data.

MH, JA, MR, and RB wrote the original draft of the manuscript.

All authors reviewed, edited, and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Data availability

The data presented in this study are available on reasonable request from the corresponding author. The data are not publicly available due to ethical and data privacy protection obligations.

Conflict of Interest Disclosures (including financial disclosures):

RB and JA received grants from the Federal State of Saxony, Germany. JS received institutional funding for investigator-initiated research from Novartis, Sanofi, Pfizer, ALK, and acted as a consultant for Novartis, Sanofi, and Lilly in a function unrelated to this study. The other authors have no conflicts of interest to disclose.

Role of Funder: The study was partially supported by funding from the Federal State of Saxony, Germany. The Federal State of Saxony had no role in the design and conduct of the study.

Clinical Trial Registration: German Clinical Trials Register, DRKS00021506; https://www.drks.de/drks_web/setLocale_EN.do; we share individual participant data if reasonable requests are received.

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Table 1

Clinical characteristics of patients with PIMS-all, PIMS-non-KD, PIMS-KD and KD.
	PIMS-all (n = 395)	PIMS-non-KD (n = 153)	PIMS-KD (n = 242)	p-value^a	KD (n = 69)	p-value^b
Age, median in years (IQR) <1 y, n (%) 1–6 y, n (%) 7–15 y, n (%) 16–19 y, n (%)	7 (4–11) 13 (3.3) 156 (39.5) 199 (50.4) 27 (6.8)	9 (5–13) 5 (3.3) 47 (30.7) 80 (52.3) 21 (13.7)	7 (4–10) 8 (3.3) 109 (45.0) 119 (49.2) 6 (2.5)	< 0.001	3 (1–4) 13 (18.8) 45 (65.2) 11 (15.9) 0	< 0.001
Sex female, n (%) male, n (%) male-to-female ratio	141 (35.7) 254 (64.3) 1:8	55 (35.9) 98 (64.1) 1:8	86 (35.5) 156 (64.5) 1:8	1.000	26 (37.7) 43 (62.3) 1:7	0.786
Ethnicity Caucasian, n (%) African, n (%) Arabic, n (%) Asian, n (%) Other, n (%)	226 (57.2) 26 (6.6) 64 (16.2) 18 (4.6) 61 (15.4)	89 (58.2) 9 (5.9) 25 (16.3) 4 (2.6) 26 (17.0)	137 (56.6) 17 (7.0) 39 (16.1) 14 (5.8) 35 (14.5)	0.631	47 (68.1) 2 (2.9) 6 (8.7) 8 (11.6) 6 (8.7)	0.025
Concomitant diseases Respiratory, n (%) Cardiovascular, n (%) Gastrointestinal, n (%) Hepatic, n (%) Renal, n (%) Neurological, n (%) Psychiatric, n (%) Hematological, n (%) Oncological, n (%) Organ/Bone marrow transplant, n (%) Autoimmune, n (%) Immunodeficiency, n (%) Immunosuppressive drug, n (%) Others, n (%)	94 (23.8) 18 (4.6) 13 (3.3) 9 (2.3) 2 (0.5) 4 (1.0) 7 (1.8) 4 (1.0) 8 (2.0) 1 (0.3) 1 (0.3) 8 (2.0) 1 (0.3) 2 (0.5) 16 (4.1)	44 (28.8) 7 (4.6) 4 (2.6) 4 (2.6) 2 (1.3) 2 (1.3) 4 (2.6) 2 (1.3) 4 (2.6) 0 1 (0.7) 4 (2.6) 1 (0.7) 1 (0.7) 8 (5.2)	50 (20.7) 11 (4.5) 9 (3.7) 5 (2.1) 0 2 (0.8) 3 (1.2) 2 (0.8) 4 (1.7) 1 (0.4) 0 4 (1.7) 0 1 (0.4) 8 (3.3)	0.430 0.990 0.550 0.720 0.070 0.640 0.310 0.640 0.510 0.430 0.210 0.510 0.210 0.740 0.350	15 (21.7) 1 (1.4) 3 (4.3) 0 0 2 (2.9) 1 (1.4) 0 1 (1.4) 0 0 3 (4.3) 0 0 4 (5.8)	0.440 0.230 0.660 0.210 0.550 0.200 0.850 0.400 0.750 0.680 0.680 0.240 0.680 0.550 0.510
PIMS, Pediatric multisystem inflammatory syndrome; KD, Kawasaki disease; ^acomparison between PIMS-non-KD and PIMS-KD; ^bcomparison between PIMS-all and KD; n; number of cases; IQR, inter-quartal range; y, years

Table 2

Clinical symptoms and significant laboratory values in patients with PIMS-all, PIMS-non-KD, PIMS-KD and KD.
	PIMS-all (n = 395)	PIMS-non-KD (n = 153)	PIMS-KD (n = 242)	p-value^a	KD (n = 69)	p-value^b
Ear-Nose-Throat (ENT), n (%)	119 (30.1)	33 (21.6)	86 (35.5)	< 0.001	32 (46.4)	0.010
Respiratory, n (%) Dyspnea, n (%) Tachypnea, n (%) Pleural effusion, n (%) Pneumonia, n (%) Pediatric acute respiratory distress syndrome (pARDS), n (%)	204 (51.6) 44 (11.1) 85 (21.5) 116 (29.4) 63 (15.9) 32 (8.1)	80 (52.3) 26 (17.0) 47 (30.7) 40 (26.1) 34 (22.2) 21 (13.7)	124 (51.2) 18 (7.4) 38 (15.7) 76 (31.4) 29 (12.0) 11 (4.5)	0.840 < 0.001 < 0.001 0.260 0.010 < 0.001	23 (33.3) 4 (5.8) 7 (10.1) 8 (11.6) 5 (7.2) 1 (1.4)	< 0.001 0.180 0.030 < 0.001 0.060 0.050
Cardiovascular, n (%) Heart failure, n (%) Arterial hypotension, n (%) Pericardial effusion, n (%) Myocardial dysfunction, n (%) Peri-/Myocarditis, n (%) Coronary artery dilatation, n (%) Coronary aneurysm, n (%)	294 (74.4) 110 (27.8) 84 (21.3) 134 (33.9) 161 (40.8) 101 (25.6) 44 (11.1) 37 (9.4)	108 (70.6) 41 (26.8) 30 (19.6) 50 (32.7) 62 (40,5) 41 (26.8) 13 (8.5) 11 (7.2)	186 (76.9) 69 (28.5) 54 (22.3) 84 (34.7) 99 (40.9) 60 (24.8) 31 (12.8) 26 (10.7)	0.160 0.710 0.520 0.680 0.940 0.660 0.190 0.430	42 (60.9) 4 (5.8) 4 (5.8) 15 (21.7) 8 (11.6) 5 (7.2) 18 (26.1) 13 (18.8)	0.020 < 0.001 < 0.001 0.050 < 0.001 < 0.001 < 0.001 0.020
Gastrointestinal, n (%) Abdominal pain, n (%) Vomiting, n (%) Diarrhea, n (%) Ascites, n (%) Gastroenteritis Appendicitis, n (%) Peritonitis, n (%) Thickening of enteric wall, n (%) Splenomegaly, n (%)	316 (80.0) 165 (41.8) 151 (38.2) 174 (44.1) 126 (31.9) 75 (19.0) 27 (6.8) 22 (5.6) 76 (19.2) 68 (17.2)	116 (75.8) 67 (43.8) 49 (32.0) 61 (39.9) 44 (28.8) 22 (14.4) 15 (9.8) 11 (7.2) 40 (26.1) 19 (12.4)	200 (82.6) 98 (40.5) 102 (42.1) 113 (46.7) 82 (33.9) 53 (21.9) 12 (5.0) 11 (4.5) 36 (14.9) 49 (20.2)	0.100 0.520 0.040 0.180 0.290 0.060 0.060 0.270 0.010 0.040	40 (58.0) 20 (29.0) 27 (39.1) 26 (37.7) 12 (17.4) 9 (13.0) 3 (4.3) 1 (1.4) 2 (2.9) 9 (13.0)	< 0.001 0.050 0.930 0.450 0.010 0.240 0.440 0.150 < 0.001 0.390
Hepatic, (%) Hepatomegaly, n (%)	82 (20.8) 64 (16.2)	26 (17.0) 15 (9.8)	56 (23.1) 49 (20.2)	0.140 0.010	13 (18.8) 11 (15.9)	0.720 0.960
Renal, n (%) Impaired renal function, n (%) Nephritis, n (%)	82 (20.8) 48 (12.2) 5 (1.3)	34 (22.2) 21 (13.7) 5 (3.3)	48 (19.8) 27 (11.2) 0	0.570 0.450 < 0.001	7 (10.1) 2 (2.9) 2 (2.9)	0.040 0.020 0.310
Neurological, n (%) Headache, n (%) Meningitis, n (%)	90 (22.8) 43 (10.9) 17 (4.3)	35 (22.9) 16 (10.5) 7 (4.6)	55 (22.7) 27 (11.2) 10 (4.1)	0.970 0.830 0.830	8 (11.6) 4 (5.8) 1 (1.4)	0.040 0.800 0.260
Psychiatric, n (%)	15 (3.8)	5 (3.3)	10 (4.1)	0.660	1 (1.4)	0.330
Musculoskeletal, n (%) Arthralgia, n (%) Arthritis, n (%) Myalgia, n (%) Myositis, n (%)	40 (10.1) 17 (4.3) 7 (1.8) 27 (6.8) 4 (1.0)	14 (9.2) 7 (4.6) 3 (2.0) 8 (5.2) 2 (1.3)	26 (10.7) 10 (4.1) 4 (1.7) 19 (7.9) 2 (0.8)	0.610 0.830 0.820 0.320 0.640	10 (14.5) 7 (10.1) 4 (5.8) 3 (4.3) 0	0.280 0.040 0.040 0.440 0.400
Hematological, n (%) Anemia, n (%) Thrombocytopenia, n (%) Disseminated intravascular coagulation, n (%)	152 (38.5) 80 (20.3) 62 (15.7) 39 (9.9)	54 (35.3) 21 (13.7) 18 (11.8) 18 (11.8)	98 (40.5) 59 (24.4) 44 (18.2) 21 (8.7)	0.300 0.010 0.090 0.320	15 (21.7) 9 (13.0) 3 (4.3) 0	0.010 0.160 0.010 0.010
Cutaneous, n (%) Rash, n (%) Desquamation, n (%) Swelling of hand / feet, n (%)	269 (68.1) 229 (58.0) 35 (8.9) 117 (29.6)	49 (32.0) 40 (26.1) 3 (2.0) 9 (5.9)	220 (90.9) 189 (78.1) 32 (13.2) 108 (44.6)	< 0.001 < 0.001 < 0.001 < 0.001	68 (98.6) 59 (85.5) 17 (24.6) 37 (53.6)	< 0.001 < 0.001 < 0.001 < 0.001
Mucosal, n (%) Enanthema, n (%) Conjunctivitis, n (%)	254 (64.3) 151 (38.2) 226 (57.2)	34 (22.2) 3 (2.0) 31 (20.3)	220 (90.9) 148 (61.2) 195 (80.6)	< 0.001 < 0.001 < 0.001	65 (94.2) 47 (68.1) 60 (87.0)	< 0.001 < 0.001 < 0.001
General, n (%) Cervical lymphadenopathy, n (%)	136 (34.4)	19 (12.4)	117 (48.3)	< 0.001	35 (50.7)	0.010
C-reactive protein, median in mg/L, (IQR) Missing variables, n (%)	187.8 (118.1-253.4) 27 (6.8)	174 (119.7-258.5) 11 (7.2)	196.5 (116.5-251.8) 16 (6.6)	0.075	122 (63.7–176.0) 2 (2.9)	< 0.001
Ferritin, median in ng/mL, (IQR) Missing variables, n (%)	508 (296.8-883.5) 115 (29.1)	537 (297.0-839.3) 45 (29.4)	485 (295.0-883.5) 70 (28.9)	0.322	211.5 (155.9-318.8) 29 (42.0)	< 0.001
NT-proBNP, median in pmol/L, (IQR) Missing variables, n (%)	556 (130.4-1,436,5) 99 (25.1)	435.1 (101.3-1,431.5) 38 (24.8)	585.7 (151.9-1,434.5) 61 (25.2)	0.015	151.4 (52.9-331.8) 27 (39.1)	< 0.001
Troponin T, median in µg/L, (IQR) Missing variables, n (%)	44.8 (16.6-175.1) 104 (26.3)	77.2 (20.6-268.5) 42 (27.5)	38.7 (16-0-144.5) 62 (25.6)	0.079	8.0 (4.9–29.0) 30 (43.5)	< 0.001
D dimer, median in mg/FEU, (IQR) Missing variables, n (%)	4.3 (2.4–8.5) 95 (24.1)	4.0 (2.2–7.6) 34 (22.2)	4.4 (2.6–8.6) 61 (25.2)	0.030	2.0 (1.3–4.2) 29 (42.0)	0.014
PIMS, Pediatric Multisystem Inflammatory Syndrome; KD, Kawasaki disease; ^acomparison between PIMS-non-KD and PIMS-KD; ^bcomparison between PIMS-all and KD; n; number of cases; pARDS, pediatric acute respiratory distress syndrome; IQR, inter-quartal range

Table 3

Therapy and outcome in patients with PIMS-all, PIMS-non-KD, PIMS-KD and KD.
	PIMS-all (n = 395)	PIMS-non-KD (n = 153)	PIMS-KD (n = 242)	p-value^a	KD (n = 69)	p-value^b
Any therapy, n (%) Duration of hospitalization, median in days (IQR) Missing variables, n (%)	364 (92.2) 10 (8–12) 72 (18.2)	139 (90.8) 9 (7–13) 33 (21.6)	225 (93.0) 10 (8–12) 39 (16.1)	0.450 0.488 n.a.	57 (82.6) 8 (6–12) 9 (13.0)	0.010 0.115 n.a.
ICU, n (%) Duration of ICU, median in days (IQR) Missing variables, n (%)	190 (48.1) 1 (0–5) 37 (9.4)	76 (49.7) 2 (0–6) 18 (11.8)	114 (47.1) 0 (0–5) 19 (7.9)	0.620 0.012	13 (18.8) 0 (0–0) 6 (8.7)	< 0.001 0.707
Pulmonary support, n (%) O₂-supplementation, n (%) High-flow, n (%) Continuous pulmonary airway pressure, n (%) Invasive ventilation, n (%)	126 (31.9) 110 (27.8) 38 (9.6) 13 (3.3) 48 (12.2)	56 (36.6) 47 (30.7) 19 (12.4) 11 (7.2) 27 (17.6)	70 (28.9) 63 (26.0) 19 (7.9) 2 (0.8) 21 (8.7)	0.110 0.310 0.130 < 0.001 0.010	7 (10.1) 7 (10.1) 1 (1.4) 0 1 (1.4)	0.000 < 0.001 0.020 0.130 0.010
Inotropes / Vasodilators, n (%)	111 (28.1)	42 (27.5)	69 (28.5)	0.820	2 (2.9)	< 0.001
Hemo- / Peritoneal dialysis, n (%)	1 (0.3)	1 (0.7)	0	0.210	0	0.680
Antivirals, n (%)	3 (0.8)	2 (1.3)	1 (0.4)	0.320	0	0.470
Antibiotics, systemic, n (%)	280 (70.9)	103 (67.3)	177 (73.1)	0.220	46 (66.7)	0.480
Immunomodulators, n (%) IVIG, n (%) IVIG-only, n (%) Corticosteroids, n (%) Corticosteroids-only, n (%) IVIG + corticosteroids, n (%) Anti-IL-1 inhibitors, n (%) Anti-IL-6 inhibitors, n (%) Anti-TNFalpha inhibitors, n (%)	352 (89.1) 322 (81.5) 52 (13.2) 262 (66.3) 118 (29.9) 234 (59.2) 7 (1.8) 3 (0.8) 2 (0.5)	129 (84.3) 114 (74.5) 20 (13.1) 98 (64.1) 52 (34.0) 83 (54.2) 3 (2.0) 1 (0.7) 0	223 (92.1) 208 (86.0) 32 (13.2) 164 (67.8) 66 (27.3) 151(62.4) 4 (1.7) 2 (0.8) 2 (0.8)	0.010 < 0.001 0.970 0.450 0.160 0.110 0.820 0.850 0.260	61 (88.4) 55 (79.7) 17 (24.6) 36 (52.2) 16 (23.2) 32 (46.4) 0 0 1 (1.4)	0.860 0.720 0.010 0.020 0.260 0.050 0.270 0.670 0.370
Hemostaseological, n (%) Heparin, n (%) Acetylsalicylic-acid, n (%)	200 (50.6) 85 (21.5) 169 (42.8)	73 (47.7) 40 (26.1) 53 (34.6)	127 (52.5) 45 (18.6) 116 (47.9)	0.360 0.080 0.010	32 (46.4) 2 (2.9) 30 (43.5)	0.520 < 0.001 0.910
Transfusion, n (%)	25 (6.3)	15 (9.8)	10 (4.1)	0.020	2 (2.9)	0.260
Other, n (%)	61 (15.4)	31 (20.3)	30 (12.4)	0.040	7 (10.1)	0.250
Outcome, Restitutio ad integrum, n (%) Symptoms (potentially reversible) at discharge, n (%) Respiratory tract symptoms, n (%) Cardiovascular symptoms, n (%) Gastrointestinal symptoms, n (%) Hepatic symptoms, n (%) Renal symptoms, n (%) Neurological symptoms, n (%) Hematological symptoms, n (%) Skin changes, n (%) Mucosal changes, n (%) Sequelae (potentially irreversible) at discharge, n (%) Cardiovascular sequelae, n (%) Cardiac failure, n (%) Coronary artery aneurysm, n (%) Other sequelae, n (%) Death, n (%)	210 (53.2) 167 (42.3) 15 (3.8) 86 (21.8) 10 (2.5) 6 (1.5) 2 (0.5) 12 (3.0) 8 (2.0) 19 (4.8) 11 (2.8) 28 (7.1) 27 (6.8) 3 (0.8) 15 (3.8) 1 (0.3) 0	88 (57.5) 60 (39.2) 10 (6.5) 27 (17.6) 7 (4.6) 4 (2.6) 0 3 (2.0) 3 (2.0) 5 (3.3) 2 (1.3) 5 (3.3) 5 (3.3) 0 2 (1.3) 0 0	122 (50.4) 107 (44.2) 5 (2.1) 59 (24.4) 3 (1.2) 2 (0.8) 2 (0.8) 9 (3.7) 5 (2.1) 14 (5.8) 9 (3.7) 23 (9.5) 22 (9.1) 3 (1.2) 13 (5.4) 1 (0.4) 0	0.170 0.330 0.020 0.110 0.040 0.160 0.260 0.320 0.940 0.260 0.160 0.020 0.030 0.170 0.040 0.430 n.a.	37 (53.6) 27 (39.1) 1 (1.4) 18 (26.1) 0 0 0 0 0 3 (4.8) 0 8 (11.6) 8 (11.6) 0 5 (7.2) 0 0	0.940 0.330 0.330 0.430 0.180 0.300 0.550 0.140 0.230 0.870 0.160 0.200 0.170 0.470 0.190 0.680 n.a.
PIMS, Pediatric Multisystem Inflammatory Syndrome; KD, Kawasaki disease; ^acomparison between PIMS-non-KD and PIMS-KD; ^bcomparison between PIMS-all and KD; n; number of cases; IQR, inter-quartal range; ICU, intensive care unit; IVIG, intravenous immunoglobulins; n.a., not applicable.

No competing interests reported.

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Comparison of Pediatric Inflammatory Multisystem Syndrome temporarily-associated with SARS-CoV-2 and Kawasaki Disease: Results from a nationwide German registry 2020-2021

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