key: cord-0942862-ngjtjiq0
authors: Ludwikowska, K. M.; Okarska-Napierala, M.; Dudek, N.; Tracewski, P.; Kusa, J.; Piwonski, K.; Afelt, A.; Cysewski, D.; Biela, M.; Werner, B.; Jackowska, T.; Suski, C.; Kursa, M. B.; Kuchar, E.; Szenborn, L.
title: Multisystem inflammatory syndrome in European White children - study of 274 cases
date: 2021-03-31
journal: nan
DOI: 10.1101/2021.03.30.21254584
sha: 14aa7c8709bae75a3dac4373553f0013ae11ee02
doc_id: 942862
cord_uid: ngjtjiq0

Despite the growing literature on multisystem inflammatory syndrome in children (MIS-C), the data in European White population is limited. Our aim was to capture MIS-C emergence in Poland (central Europe) and to describe its characteristics with a focus on severity determinants. Patients who met the MIS-C definition (fever, multiorgan failure, inflammation, and proven SARS-CoV-2 infection or contact) were reported retrospectively and prospectively in an online survey. Study definitions fulfilment was automatically evaluated by a dedicated software. For the assessment of univariate relationships, either directed or divided by sex, age, or disease severity, we used the test for two categorical variables and the Kruskal-Wallis test for categorical-continuous variable pairs. The analysis involved 274 children, 62.8% boys, median age 8.8 years. Besides one Asian, all were European White. Merely 23 (8.4%) required paediatric intensive care treatment (PICU). They were older (11.2 vs. 8.4 years), and at hospital admission had higher respiratory rate (30 v. 20/minute), lower systolic blood pressure (89 vs. 100 mmHg), prolonged capillary refill time (40% vs. 11%), and decreased consciousness (22% vs. 5%). Teenage boys had more common cardiac involvement (fraction 25.9% vs. 14.7% ) and macrophage activation syndrome (31.0% vs. 15.2%) than others. Boys were also more often hospitalised in PICU with age (from median 11.2 years to 9.1). The severity of MIS-C is not as uniform as it seemed, ethnicity and sex may affect MIS-C phenotype. Management might not be universally applicable and should rather be adjusted to the specific population.

Paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or multisystem inflammatory syndrome in children (herein referred to as MIS-C), is a new paediatric entity which has emerged in countries particularly hit by coronavirus disease 2019 (COVID- 19) pandemic. [1] [2] [3] [4] [5] [6] [7] [8] [9] Despite similarities to other inflammatory conditions, e.g. Kawasaki disease (KD), macrophage activation syndrome (MAS), or toxic shock syndrome, MIS-C has its distinct features. 8, 9 MIS-C is characterised by a sudden onset of rapidly progressing multisystem inflammation which particularly affects the cardiovascular system, resulting in cardiac dysfunction and shock. Milder forms of fever and inflammation were also described, however in the largest published cohorts majority of patients necessitated treatment in a paediatric intensive care unit (PICU). [4] [5] [6] [7] [8] [9] In order to perceive the emergence of MIS-C in our country, we have launched a national surveillance of inflammatory disorders in children (MultiOrgan Inflammatory Syndromes COVID-19 Related Study, MOIS-CoR). Following COVID-19 second wave in Autumn 2020, a rise in MIS-C prevalence has emerged in Poland. Here we report the results of the survey, revealing a consistent picture of MIS-C in our population, yet with some unique local characteristics.

The surveillance was launched on 25th May 2020. The inclusion criteria are presented in Appendix (p 2). Ethical approval was obtained from the Bioethics Committee at Wroclaw Medical University (CWN UMW BW: 313/2020). Waiver of informed consent was obtained with only deidentified data transmitted and analysed.

Children aged 0-18 years old with inflammatory conditions were voluntarily reported from 42 cities from all over the country (appendix p 8). Anonymised patients' data were retrospectively and prospectively extracted from health records and collected through an online questionnaire developed for that purpose. Demographic data, clinical characteristics, laboratory parameters, cardiovascular evaluation results, treatment and outcome data were collected. Vital signs and laboratory parameters were obtained at admission and at their respective peaks. Here we report the data covering period between 4th March 2020 (when the first COVID-19 case was confirmed in Poland) and 20th February 2021. The analysis was data-driven. Nine of the presented cases were included in our previous cursory report. 10 

For the sake of this study, we adopted World Health Organization (WHO) MIS-C case definition 3 , as follows:

• children 0-18 years old with fever lasting at least three days AND • at least two of the following: o rash or bilateral conjunctivitis, or mucocutaneous inflammation signs o hypotension defined by a minimal systolic blood pressure (sBP) below 70+2×age (in years) mmHg or below 90 mmHg for children older than ten years o features of myocardial dysfunction, pericarditis, or coronary artery abnormality (CAA), based on echocardiographic findings or elevated 

We defined lymphopenia as lymphocyte count <1.5 ×10 9 /L, anaemia according to age-related norms, thrombocytopenia as platelets <150 ×10 9 /L, elevated alanine transaminase as ≥40 U/L, hyponatremia as serum sodium <135 mmol/L, hypoalbuminemia as serum albumin <3.5 g/dL, elevated BNP/NT-proBNP as >150 ng/mL. A threshold of 50 ng/L defined elevated both T and I troponin. Renal dysfunction was defined by estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m 2 , calculated using the revised Schwartz formula.

Echocardiography results were categorised based on descriptive results and left ventricular ejection fraction (EF) and coronary artery measurements whenever available. Heart dysfunction was defined as EF <55% and severe heart dysfunction as EF <35%. Coronary artery Z-score was calculated using Dallaire equation or Boston Children's Hospital Z-score calculator, depending on the body surface area. Dilation was defined by Z-score between 2 to 2.5, while aneurysm by Z-score ≥2.5. 11 The worst available EF and the largest coronary Z-scores were included. The echography results were assessed by two independent cardiologists.

Diagnostic criteria of KD in its typical and atypical (aKD) form were adapted from American Heart Association (AHA) guidelines. 11 MAS was diagnosed based on Paediatric Rheumatology International Trials Organization criteria (consult appendix p 2). 12 The level of consciousness was evaluated using the AVPU scale.

Nutritional status was assessed using the body-mass index (BMI), converted into Z-scores based on the WHO reference standards for children younger than 5 years 13 and national reference standards for older children. 14

We describe variables in relation to the sum of cases for which the variable was recorded. We assumed missing values to be distributed randomly and independently from the data, and propagated them through aforementioned clinical definitions according to Łukasiewicz logic. Fulfilment of all aforementioned study definitions was automatically evaluated by a dedicated software. Due to an exploratory nature of this study, we have not adjusted p-values for multiple comparisons.

As of 20th February 2021, 399 children have been registered to the surveillance, 342 of whom fulfilled the inclusion criteria and 274 fulfilled MIS-C diagnostic criteria ( Figure 1 and appendix p 4). The following results apply only to the cohort of 274 children, aged from 7 months to 17.6 years, with MIS-C.

Demographic characteristics of the MIS-C cohort are presented in 

The median time between first symptoms and hospital admission was five days, and the median fever length was seven days. The vital signs at admission and at 5 . CC-BY 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ; their respective peaks are presented in Table 2 . Complete clinical characteristics of children with MIS-C are presented in Table 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Laboratory parameters at admission and at respective peaks are summarised in Table 2 

Male patients were diagnosed with MIS-C more often than expected from demographic structure, but only in the older age bracket ( Figure 2 ). We have identified some characteristics which corresponded with this discrepancy (Figure 3 , see also Table 1 and Table 2 for sex-adjusted p-value).

Teenage boys over 12 years old more prevalently had cardiac involvement ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021.

in severely immunocompromised child, and one in previously healthy teenager with fulminant multiorgan dysfunction, both with positive RT-PCR test result for SARS-CoV-2. In either case, it was impossible to determine whether the cause of death was a cytokine storm due to COVID-19 or MIS-C; they fulfilled the MIS-C criteria though, and hence were included in this analysis.

Children who were hospitalised in PICU were significantly older (from median 11.2 years [IQR 10.1-12.6] to 8.4 [5.0-11.9], p<0.01). The PICU admission rate did not significantly differ for patients with comorbidities, including obesity (Table 1 

In this study we have described the largest published so far cohort of European White children with confirmed MIS-C. Despite being initially reported as Kawasaki-like disease, MIS-C appeared to be a distinct entity soon after. 8, 9 Children in our cohort fulfilled KD/aKD diagnostic criteria more frequently than in other reports, but they concomitantly presented with unique features typical for MIS-C. On the other hand, in contrast to Western European and the United States (US) reports, the severity of the disease appeared substantially milder, as expressed by only 8.4% of patients hospitalised in PICU and two deaths. Moreover, the clinical and laboratory picture was more uniform across age groups in our cohort. [4] [5] [6] 8, 9 These discrepancies might be related to more homogenous genetic and racial characteristics of the Polish population. Children of Black, South Asian and/or Hispanic ethnicity predominated in the clusters of MIS-C reported thus far. [4] [5] [6] 8, 9 Non-Hispanic White children comprised only 13-30% of cases in the most numerous MIS-C cohorts and systematic reviews. [4] [5] [6] 8, 9 Importantly, the proportion of Black and Hispanic ethnicity in MIS-C groups was significantly higher than in local societies. 7 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ;

whether this overrepresentation of ethnic minorities and underrepresentation of non-Hispanic White children among MIS-C patients reflect genetic predisposition or higher exposure to SARS-CoV-2, as COVID-19 disproportionately affected Hispanic and Black subpopulations. 15, 16 Two hundred seventy-four MIS-C cases captured in Poland with a 7.31 million children population as compared to 2060 cases reported in the USA with 74 million children at the same time, 1,17 suggest that MIS-C prevalence in our country could have reached a level comparable to the US, despite specific, homogenous racial background.

Another issue is whether race/ethnicity is associated with the severity of the disease. Some authors suggest that children of Black ethnicity present a more severe clinical course of MIS-C, 4,6 whereas others 18 argue against it. Our cohort was almost exclusively composed of European White children which is a major demographic characteristic distinguishing it from other MIS-C cohorts. This should be considered as a possible explanation of milder clinical presentation with favourable outcome, however, this conclusion should be treated with caution and requires further analysis.

Another feature of our cohort was the relatively small proportion of obese children as compared to majority of reports from other countries (6.7% vs. 18-26%). 4, 6, 9 This could have possibly resulted from lower obesity prevalence among children in Poland (up to 13%). 19 Interestingly, in the US, obesity is more prevalent in Black (up to 22%) and Hispanic (up to 26%) children as opposed to non-Hispanic White (up to 14.1%). 20 It is unknown whether obesity is a risk factor for developing MIS-C nor if it is connected to its severity. In our study, we found no association between BMI Z-score or obesity and severity of the disease.

Polish recommendations for MIS-C treatment are similar to those from the USA or the United Kingdom. 21, 22 Treatment used in our cohort did not differ substantially from treatment reported by other authors -most children received IVIG and a large proportion also got steroids. Fewer children required more than two different immunomodulatory agents. [4] [5] [6] 8, 9 Moreover, the median day of hospital admission since the first symptoms was similar to other reports. 6, 23 Hence, the therapeutic approach is an unlikely factor of a more favourable outcome in Polish children with MIS-C.

Despite relatively uniform clinical presentation in terms of mucocutaneous, gastrointestinal, or respiratory manifestations across the age groups, cardiovascular involvement significantly increased with age, which is in line with Dufort and Abrams findings. 4, 23 Laboratory markers of the heart injury were elevated in the majority of patients, whereas hypotension was present in 40.7% and decreased EF -in 22.6% of patients.

Cardiac involvement is a major factor determining MIS-C severity, however data about cardiovascular complications are inconsistent. This is partially due to varying (sometimes unspecified) definitions used by different authors, 4,6,23,24 and varying inclusion criteria -either broader than WHO MIS-C case definition, 24 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ; narrowed only to the most severe cases. 7 Decreased sBP, occasionally defined as a shock, was reported in 36-86% of patients with MIS-C, whereas decreased left ventricular function -20-45%. [4] [5] [6] [7] [8] 24 Our findings place Polish children with MIS-C within the "milder end" of the acute cardiovascular complications spectrum described above.

Similarly, the prevalence of coronary artery involvement in MIS-C is debatable. Undoubtedly aneurysms may complicate the disease, cases of giant aneurysms have been described, 24 but the true prevalence of aneurysms is unknown. CAA prevalence may be overestimated, as coronary dilation may be a result of an acute febrile condition or myocarditis. 25 Both coronary artery aneurysms and dilations were less prevalent in our group than in other reports. [4] [5] [6] 8, 9, 24 Interestingly, we have observed that some MIS-C features differed between girls and boys in adolescence and, to our knowledge, this is the first report of sex-related discrepancies in MIS-C presentation. Teenage boys had more frequent cardiac involvement, MAS and PICU hospitalization rate. The more severe course of COVID-19 in adult males is well established. 26 While some authors postulate that it is linked with genetic and immunological background, 27 others suggest that sex hormones may play a role. 28, 29 COVID-19 and MIS-C are separate entities, but share some similarities being hyperinflammatory conditions. In our cohort, the distinction between children of different sex appeared at pubertal age, which might support the hormonal theory.

Finally, we aimed to identify clinical and laboratory features specific to patients who required intensive care. Similarly to previous reports, the only demographic characteristic associated with PICU admission was older age. 4, 6 The median time of hospital admission since the first symptoms did not differ significantly for PICU patients. They could be distinguished by their vital signs at hospital admission: decreased level of consciousness, longer CRT, higher respiratory rate and lower sBP. In concordance with other reports, the severity of disease was correlated with the particularly high inflammatory markers. 6, 8 The involvement of the laboratory evaluation at admission is one of strengths of our study; we found that initial values of inflammatory markers, D-dimers, albumin, eGFR, and markers of the heart injury correlated with the progression to severe disease.

The study relied on voluntary participation, hence a number of MIS-C cases might have been missed or biased by non-random sampling. Some patients meeting the MIS-C criteria may have been misclassified, e.g. due to unequal access to SARS-CoV-2 testing or missing data. Whenever possible, outliers in our data were verified at source. We have not obtained the data about catecholamine treatment. The broad MIS-C case definition and advanced epidemiological situation allowed children with alternative diagnoses and coincidental positive SARS-CoV-2 results to be included in our cohort. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ;

Precise epidemiological data on COVID-19 prevalence among age groups in Poland is lacking. We have also assumed homogeneity of risk of contracting the virus in the juvenile population.

The severity of MIS-C is not as uniform as it seemed based on previous reports. In particular, ethnicity and sex may affect MIS-C phenotype. Consequently, management protocols might be not universally applicable, and should rather be adjusted to the specific population.

. CC-BY 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ; Figure 3 . Incidence of the selected events within the study group, according to age and sex Abbreviations: KD/aKD, Kawasaki disease/atypical Kawasaki disease; MAS, macrophage activation syndrome; MIS-C, multisystem inflammatory syndrome in children; PICU, paediatric intensive care unit a Musculo−osteoarticular symptoms encompassed: muscle pain, arthralgia, or arthritis b Lower respiratory symptoms encompassed: chest pain, cough, or dyspnea c Cardiac involvement encompassed left ventricular ejection fraction <55%, or coronary artery abnormalities (dilation or aneurysm) or pericardial effusion d The highest available result of troponin concentration was included in this analysis e Defined by a minimal systolic blood pressure below 70+2×age (in years) mmHg or below 90 mmHg for children over 10 years old f Diagnostic criteria of KD/aKD were adapted from American Heart Association guidelines 11 g MAS was diagnosed based on Paediatric Rheumatology International Trials Organization criteria 12 16 . CC-BY 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 31, 2021. ; activation syndrome; med, median; MIS-C, multisystem inflammatory syndrome in children; PICU, paediatric intensive care unit; y, years old a Defined by a minimal systolic blood pressure below 70+2×age (in years) mmHg or below 90 mmHg for children over 10 years old b Dilation was defined as a Z-score between 2 to less than 2.5, while aneurysm as Z-score ≥2.5 11 c Diagnostic criteria of KD in its typical and atypical (aKD) form were adapted from American Heart Association guidelines 11 d MAS was diagnosed based on Paediatric Rheumatology International Trials Organization criteria 12 e DIC was diagnosed using modified DIC score 178.0 (128. 5 Abbreviations: AlAT, alanine transaminase; AVPU, AVPU scale; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; IQR, interquartile range; med, median; MIS-C, multisystem inflammatory syndrome in children; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PICU, paediatric intensive care unit * lowest values were obtained ** highest values were obtained a Troponin >50 ng/L b BNP/NT-proBNP >150 ng/mL

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We thank to all the pediatricians who contributed to our work by reporting patients, especially to: Alicja