Cardiac involvement in children with paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): data from a prospective nationwide surveillance study

to 10.4% and 17.6% in the ICU-moderate and ICU-severe group, respectively) (p = 0.011). CONCLUSION: Cardiac complications in children presenting with PIMS-TS are common and may worsen during the hospitalisation. Irrespective of initial severity, resolution of left ventricular systolic dysfunction is observed, often occurring rapidly during the hospitalisation. Most of the coronary artery abnormalities regress; however, some are still present at follow-up, emphasising the need for prolonged cardiac evaluation after PIMS-TS.

METHODS: This prospective nationwide surveillance study included children and adolescents less than 18 years of age who were hospitalised with PIMS-TS in Switzerland between March 2020 and March 2022.Data was collected from all 29 paediatric hospitals through the Swiss Paediatric Surveillance Unit (SPSU) during hospitalisation and approximately six weeks after discharge.The data was analysed after categorising the participants into three groups based on their admission status to the intensive care unit (ICU) (non-ICU, ICU-moderate) and the requirement for invasive ventilatory and/or inotropic support (ICU-severe).RESULTS: Overall, 204 children were included of whom 194 (95.1%) had follow-up data recorded.Median age was 9.0 years (interquartile range [IQR] 6.0-11.5)and 142 (69.6%) were male.In total, 105/204 (51.5%) required ICU admission, of whom 55/105 (52.4%) received inotropic support and 14/105 (13.3%) mechanical ventilation (ICUsevere group).Echocardiography was performed in 201/ 204 (98.5%) children; 132 (64.7%) had a cardiac abnormality including left ventricular systolic dysfunction (73 [36.3%]), a coronary artery abnormality (45 [22.4%]), pericardial effusion (50 [24.9%]) and mitral valve regurgitation (60 [29.9%]).Left ventricular systolic dysfunction was present at admission in 62/201 (30.8%) children and appeared during hospitalisation in 11 (5.5%) children.A coronary artery abnormality was detected at admission in 29/ 201 (14.2%) children and developed during hospitalisation or at follow-up in 13 (6.5%) and 3 (1.5%)children, respectively.None of the children had left ventricular systolic dysfunction at follow-up, but a coronary abnormality and pericardial effusion were found in 12 (6.6%)and 3 (1.7%)children, respectively.School absenteeism at the time of follow-up was more frequent in children who had been admitted to the ICU (2.5% in the non-ICU group compared

Introduction
Since the description of the first cases of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in April 2020, this disease has affected thousands of children and adolescents worldwide.In the United States of America alone, the Centers for Disease Control and Prevention (CDC) reported more than 9000 cases on the COVID Data Tracker as of 3 October 2022.PIMS-TS usually occurs 4 to 8 weeks after SARS-CoV-2 infection [1,2].Clinical features include fever and multiple organ dysfunction, including cardiac involvement often requiring intensive care unit (ICU) admission [3,4].The pandemic has generated several successive waves of various intensities and SARS-CoV-2 will continue to circulate, with an ongoing risk of PIMS-TS.Due to the potential severe course of the disease, efforts must be maintained to understand how PIMS-TS affects the heart and what long-term consequences are to be expected.The acute presentation of PIMS-TS has been described exhaustively, but the short-, medium-and long-term manifestations are still poorly understood and rely on reports from a small number of children [5,6].This study provides a detailed description of cardiac involvement according to disease severity in a large cohort of children and adolescents with PIMS-TS.It focuses on the detailed short-term evolution during the hospital stay and in the first two months thereafter.

Study design and population
The prospective national observational cohort study included children and adolescents below 18 years of age who were hospitalised with PIMS-TS in Switzerland from 1 March 2020 to 31 March 2022.PIMS-TS was defined according to national guidelines [7]: -presence of fever; -laboratory evidence of inflammation; -single or multiorgan dysfunction; -exclusion of an alternative diagnosis; -evidence of current or recent SARS-CoV-2 infection or exposure to SARS-CoV-2.
Data was collected as part of a larger study on SARS-COV-2 infections in children through the Swiss Paediatric Surveillance Unit (SPSU, https://www.spsu.ch)[8,9].All 29 paediatric hospitals in Switzerland were asked to submit cases monthly using an electronic clinical report form through REDCap (Research Electronic Data CAPture) [10] (see supplementary data for the questionnaire).For each patient, detailed epidemiological and clinical data, laboratory values, transthoracic echocardiographic findings, treatment and outcome were recorded during hospitalisation and four to six weeks after hospital discharge.Normal values for troponin T and N-terminal pro B-type natriuretic peptide (NT-proBNP) were defined according to international normal ranges for age [11].Coronary artery dimensions and left ventricular ejection fraction (LVEF) were taken from the echocardiography report, which was completed by a paediatric cardiologist.Coronary artery involvement was classified according to the AHA guidelines [12] and using the z-score system by Dallaire and Dahdah [13], which has the following categories: no involvement: z-score <2; dilation: z-score ≥2 to <2.5; small aneurysm: z-score ≥2.5 to <5; medium aneurysm: zscore ≥5 to <10; giant aneurysm: z-score ≥10.A normal LVEF was defined as an LVEF of 55% or higher.Mild systolic dysfunction was defined as LVEF ≥45% to <55%; moderate systolic dysfunction as LVEF >35% to <45%; and severe systolic dysfunction as LVEF ≤35%.Right ventricular systolic function and right or left ventricular diastolic function were deemed abnormal or not on the basis of the echocardiography report.For the analysis, children were stratified into three groups according to disease severity: "non-ICU": children not admitted to the ICU; "ICU-moderate": children admitted to the ICU but not requiring invasive ventilation or inotropic support; "ICU-severe": children admitted to the ICU and requiring invasive ventilation and/or inotropic support.

Statistical analysis
Descriptive statistics were used to summarise the epidemiological and clinical data (median and interquartile range [IQR] for continuous data and proportions for categorical data).Categorical data were compared using the Chisquare test and comparisons between the three groups were assessed using the Kruskal-Wallis rank-sum test for nonnormally distributed data.The Pearson and Spearman correlation coefficients were used for normally and non-normally distributed data, respectively, to assess the association between inflammatory biomarker values and coronary artery abnormalities or left ventricular systolic dysfunction.Missing data is mentioned in the tables summarising echocardiographic findings.To aid readability of tables, all other missing data are mentioned only in the supplementary data section.All analyses were performed with R software (version 2022.07.1).
At follow-up, coronary artery abnormalities were reported in 12 (5.9%)children.Details on coronary artery involvement and treatment during hospitalisation are summarised in the supplementary data (table S6).
Pericardial effusion was present in 50 (25.0%)children, occurring more frequently in children admitted to the ICU (p = 0.035).Three (1.7%) children with pericardial effusion during hospitalisation had persistent pericardial effusion at follow-up (table 3).No child had pericardial effusion that required an intervention.
An abnormal NT-proBNP peak value was reported in 182 (97.8%) children and an abnormal troponin T value in 183 (69.4%) (table S5).The median troponin T and NT-proB-NP values were higher in the ICU-severe group than in the ICU-moderate and non-ICU groups (table S5).There was no correlation between coronary artery involvement and inflammatory markers (C-reactive protein ICU-severe n = 10) [14].

Outcome and follow-up
The median length of hospitalisation was 6.0 (IQR 5.0-8.0)days and the duration of ICU admission was 2.0 (1.5-5.

Discussion
This large multicentre national study presents detailed cardiological data and follow-up from active surveillance of children diagnosed with PIMS-TS during the first two years of the COVID pandemic in Switzerland.The overall epidemiological data are comparable with that of other European and North American studies, including the rate of cardiac involvement [15][16][17][18][19].Although the number of children of Black ethnicity is not available in Switzerland, they were likely overrepresented in our cohort, a finding that is in line with data from a previous meta-analysis [20].
Left ventricular systolic dysfunction was one of the key cardiac findings in this cohort of children with PIMS-TS,

Original article
Swiss Med Wkly.2023;153:40092 reported in approximately one in three children.This finding is also frequently reported in other studies ranging from 13% to 80% [15,16,[21][22][23][24].Most commonly, detection of left ventricular systolic dysfunction has been described on admission with rapid resolution before discharge [25], as documented in most of our patients.One novel finding in our cohort is a decrease in left ventricular systolic dysfunction several days after admission, which has rarely been seen previously [24].This deterioration of cardiac function after admission emphasises the need for regular echocardiographic assessment during hospitalisation in patients presenting with PIMS-TS as left ventricular systolic dysfunction, particularly in children with more severe disease.
In our cohort, coronary artery involvement occurred regardless of the severity of illness.Interestingly, there was no correlation between coronary artery involvement and anti-inflammatory markers like CRP, ferritin and ESR.However, children with coronary artery aneurysm were more likely to be admitted to the ICU.One novel finding in our study is that coronary artery involvement can occur several days after admission.This has only rarely been reported previously: one study described a series of three children who presented with coronary artery dilation after initial presentation and treatment with IVIG [26].
We found that few children with coronary artery aneurysms had persistent aneurysms at follow-up.Most studies with short-term follow-up of coronary artery abnormalities in PIMS-TS patients describe a rapid regression to normal size of the coronary arteries -as was seen in our cohort [27][28][29][30][31][32].Only a few coronary aneurysms persisted in our short-term follow-up; most regressed to normal size.However, regression to normal size does not equate to resolution and absence of long-term coronary artery sequelae.The pathophysiology of coronary artery aneurysms in PIMS-TS is not well understood.The occurrence may be caused by vasodilation in a highly proinflammatory milieu as described in febrile children [33].Alternatively it may occur as a result of the destruction of the arterial wall by inflammatory cells as is known to occur in Kawasaki disease [34].It is supposed that coronary artery dilation, as it is mostly seen in children with PIMS-TS, resolves without consequences whereas coronary artery aneurysms caused by the destruction of the arterial wall are known to increase the long-term risk of thrombosis, coronary artery steno- sis due to vascular remodelling or endothelial dysfunction even in case of regression to normal diameter [12].
In our cohort, pericardial effusion was present in one in four children but was not haemodynamically relevant and did not require intervention.In the literature, pericardial effusion is generally reported as mild and has been described in 23% to 31% of patients with PIMS-TS with rapid resolution during hospitalisation [15,16,35].In contrast, in our cohort the pericardial effusion was still present at discharge in some cases, with resolution at follow-up echocardiography in most cases.Mitral valve regurgitation was frequently reported but most commonly classified as mild, which was also seen in another study [15].Moderate or severe mitral valve regurgitation was rare and only seen in patients admitted to the ICU.One study demonstrated that the resolution of mitral valve regurgitation, which follows the development of the myocardial dysfunction, lags the resolution of the left ventricular dysfunction.But almost all patients showed a complete resolution of the mitral valve regurgitation within six months [36].
We found cardiac markers including troponin T and NT-proBNP to be higher in children admitted to the ICU.Cardiac biomarkers are frequently elevated in children with PIMS-TS [37].One study reported that NT-proBNP values were higher in children with cardiac involvement compared to those without [38].Similarly, further studies found an association between the severity of left ventricular systolic dysfunction and higher values of troponin T and NT-proBNP [39,40].The rapid resolution of the left ventricular systolic dysfunction and the cardiac biomarker levels documented in our study lends weight to the hypothesis that the myocardial injury results from a temporary myocardial oedema caused by severe inflammation rather than from direct virus-mediated myocardial damage [41].
ECG abnormalities were less commonly reported in our cohort with one in five children having an abnormal ECG.
In the literature, abnormal ST-and T-wave segments are more frequently noted, up to 46%, as is atrioventricular block, up to 25% [15,24,42,43].One study found that an atrioventricular block was more frequent in children admitted to the ICU [43].In our cohort, children with atri-oventricular block were also more frequently admitted to the ICU but the reason for ICU admission was most likely related to left ventricular systolic dysfunction and/or shock requiring inotropic support.Moreover, the atrioventricular conduction abnormalities were usually present at admission or prior to corticosteroid treatment, except for two children who developed atrioventricular block two days after initiation of treatment with corticosteroids.The proposed mechanism of such atrioventricular conduction abnormalities is that the hyperinflammatory response leads to widespread myocardial injury as well as oedema of the conduction tissue [44].
The diversity of treatment regimens observed in our study reflects the absence of evidence-based recommendations regarding PIMS-TS treatment.Observational study and expert consensus recommendation had guided treatment strategy [45,46].The results of a recent randomised controlled trial comparing methylprednisolone and IVIG treatment are expected soon and will potentially influence the future management of children with PIMS-TS [14].
The high rate of sport limitation in our study was mainly due to physical activity being advised against for three to six months if cardiac involvement was documented, as suggested by national and international guidelines [45,47].
Children without a cardiac abnormality were recommended to stop physical activity for two weeks only [7].Interestingly, persisting clinical symptoms on follow-up did not correlate with initial disease severity.

Strengths and limitations
The strengths of this study are a relatively large number of children included with detailed clinical data available.
Moreover, almost all children included had complete follow-up data available.Despite the active and established surveillance system, some cases might not have been captured in our study.Our classification of disease severity may not be applicable to other countries as the decision to admit apatient to the ICU instead of a standard ward might be determined by local practices and therefore differ between centres.However, the definition of severe cases is likely comparable as ventilation and inotropic support are clear definitions.ECG abnormalities were reported according to medical record and not all ECG were reviewed by a cardiologist, therefore we might have underestimated the rate of abnormalities.Coronary artery involvement in children is mostly assessed by transthoracic echocardiography; cardiac MRI was rarely done, therefore this data was not included for analysis.

Conclusion
Our study shows that cardiac involvement occurs in the majority of children and adolescents with PIMS-TS, the extent of which is central to the course of the disease.In the acute stage, ventricular dysfunction is most prominent, which increases the risk for ICU admission.For the longerterm consequences, coronary artery aneurysms are more important as they carry an increased risk of coronary artery stenosis and thrombosis.With a timely diagnosis and adequate therapy of PIMS-TS, recovery was documented in a few weeks.Close monitoring and regular follow-ups of children with PIMS-TS particularly those with coronary artery changes is required due to the possibility of longterm cardiac consequences.

Figure 1 :
Figure 1: Number of children with PIMS-TS according to ICU admission over time.ICU: intensive care unit; PIMS-TS: paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.

Figure 2 :
Figure 2: Evolution of left ventricular systolic dysfunction over time, by disease severity.To make trends visible, we assigned a value of 55% (= normal) when a patient with left ventricular systolic dysfunction had recovered at the next echocardiography.(Non-ICU: child not admitted to the ICU; ICU-moderate: child admitted to the ICU without need for mechanical ventilation and/or inotropic support; ICU-severe: child admitted to the ICU with need for mechanical ventilation and/or inotropic support.)For discharged the closest echocardiography before discharge was used.

Figure 3 :
Figure 3: Summary of echocardiographic and laboratory findings during admission, hospitalisation and follow-up according to disease severity.(Non-ICU: child not admitted to the ICU; ICU-moderate: child admitted to the ICU without need for mechanical ventilation and/or inotropic support; ICU-severe: child admitted to the ICU with need for mechanical ventilation and/or inotropic support.)*Non-ICU n = 99; ICU-moderate n = 50; ICU-severe n =55.**Troponin T reference value <14 ug/l; percentage calculated using n abnormal/total.***NT-proBNP reference value according to age [11]; percentage calculated using n abnormal/total.

Table 1 :
Spearman r coefficient of -0.2 and -0.1 for ESR and ferritin, respectively).However, a trend of increased CRP values and left ventricular systolic dysfunction was found (Pearson r coefficient of 0.22).No correlation was found between ESR or ferritin values and left ventricular systolic dysfunction (Spearman r coefficient of 0.1 and 0.04, respectively).Figure3summarises the key echocardiographic and laboratory abnormalities documented during hospitalisation and follow-up according to disease severity.Baseline One child with partial abnormal pulmonary venous return presented with hypotensive shock requiring inotropic support.One child with right aortic arch presented with coronary artery dilation and mild mitral valve regurgitation.
0) days.No child required treatment with extracorporeal membrane oxygenation and no deaths occurred.Follow-up data were available from 194 (95.1%) children (table4).Limitation in daily life activities because of fatigue was reported in 15 (7.9%) children without differ-

Table 2 :
Echocardiographic findings in children with PIMS-TS at admission.(Non-ICU: child not admitted to the ICU; ICU-moderate: child admitted to the ICU without need for mechanical ventilation and/or inotropic support; ICU-severe: child admitted to the ICU with need for mechanical ventilation and/or inotropic support.)

Table 3 :
Echocardiography findings during hospitalisation and follow-up (n represents an abnormal echocardiographic finding at each timepoint, not necessarily a newly diagnosed abnormality).

Table 4 :
General activity and symptoms at follow-up.Missing data is not included in this table; for further details on missing data, see tableS4.(Non-ICU: child not admitted to the ICU; ICU-moderate: child admitted to the ICU without need for mechanical ventilation and/or inotropic support; ICU-severe: child admitted to the ICU with need for mechanical ventilation and/or inotropic support.) Swiss Medical Weekly • www.smw.ch• published under the copyright license Attribution 4.0 International (CC BY 4.0)

Table S1 :
Treatment according to disease severity.

Table S2 :
ECG findings during hospitalisation and follow-up.

Table S3 :
Treatment on-going at follow-up.

Table S4 :
General activity and symptoms at follow-up.

Table S5 :
Cardiac biomarkers values during hospitalisation and at follow-up according to disease severity

Table S6 :
Details of coronary artery involvement during hospitalisation and follow-up.