Multisystem Inflammatory Syndrome in Children and SARS-CoV-2 variants: a two-year ambispective multicentric cohort study in Catalonia, Spain.

doi:10.21203/rs.3.rs-2082206/v1

Purpose

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe disease temporarily related to SARS-CoV-2. We aimed to describe the epidemiological, clinical and laboratory findings of all the MIS-C cases diagnosed in children < 18 years-old in Catalonia (Spain) to study their trend throughout the pandemic.

Methods

Multicenter ambispective observational cohort study (April 2020-April 2022). Data were obtained from the COVID-19 Catalan surveillance system and from all the hospitals in Catalonia. We analyzed MIS-C cases regarding SARS-CoV-2 variants for demographics, symptoms, severity, monthly MIS-C incidence, ratio between MIS-C and accumulated COVID-19 cases, and associated rate ratios (RR).

Results

Among 555,848 SARS-CoV-2 infections, 152 children were diagnosed with MIS-C. Monthly MIS-C incidence was 4.1 (95%CI: 3.4–4.8) per 1,000,000 people, and 273 (95%CI: 230–316) per 1,000,000 SARS-CoV-2 infections (i.e., one case per 3,700 SARS-CoV-2 infections). During the Omicron period, MIS-C RR was 8.2 (95%CI: 5.7–11.7) per 1,000,000 SARS-CoV-2 infections, significantly lower (p < 0.001) than for previous variant periods, in all age groups. Median [IQR] age of MIS-C was 8 [4–11] years, 62.5% male, and 80.2% without comorbidities. Common symptoms were gastrointestinal findings (88.2%) and fever > 39^oC (81.6%), nearly 40% had an abnormal echocardiography and 7% coronary aneurysm. Clinical manifestations and laboratory data were not different throughout the variant periods (p > 0.05).

Conclusions

The rate ratio between MIS-C cases and SARS-CoV-2 infections was significantly lower in the Omicron period for all the age groups, including those not vaccinated, suggesting that the variant could be the main factor for this shift in the MISC trend. Regardless of variant type, the patients had similar phenotypes and severity throughout the pandemic.

MIS-C associated with COVID-19

SARS-CoV-2 variants

pediatrics

epidemiology

severity

What is known

Before our study, only two publications have investigated the incidence of MIS-C regarding SARS-CoV-2 variants in Europe, one from South East England and another from Denmark.

What is new

To our knowledge this is the first study investigating MIS-C incidence in Southern Europe, with the ability to recruit all the MIS-C cases in a determined area, and analyzing the rate ratio for MIS-C among SARS-CoV-2 infections throughout variant periods.

We found a lower rate ratio of MISC/infections SARS-CoV-2 in the Omicron period for all age groups including those not eligible for vaccination.

In December 2019, the new SARS-CoV-2 emerged in China. So far, severe COVID-19 disease in children remains infrequent. In contrast with adults, most children are asymptomatic or exhibit mild symptoms during the acute phase of the infection [1].

However, SARS-CoV-2 has been temporarily associated with MIS-C, which develops approximately 2 to 6 weeks after mild or asymptomatic SARS-CoV-2 infection [2]. The case definition of MIS-C has been established by different institutions such as the WHO (May 15, 2020) [3], the US CDC (May 14, 2020) [4], and the Royal College of Paediatrics and Child Health in the UK (May 1, 2020) [5]. The clinical features of this syndrome have been widely defined and described in several report series, overlapping features of KD, toxic shock syndrome, bacterial sepsis, and macrophage-activation syndrome [6–9]. Recently, it has also been described in some patients after being vaccinated with mRNA vaccines [10].

Even so, several differential characteristics have been observed in MIS-C cases, leading more frequently to shock due to myocardial dysfunction [9]. Additionally, children require timely recognition and prompt start of immunosuppressive treatment, such as IVIG, high dose of methylprednisolone and/or IL-1 inhibitor drugs in refractory cases.

MIS-C incidence among SARS-CoV-2 infections has been difficult to determine throughout the pandemic, given the high rate of asymptomatic infection in the pediatric population. In Catalonia (Spain), systematic screening in the schools for all the class-mates of COVID-19 cases was maintained from September 2020, after the first pandemic wave [11], to January 2022. This protocol enabled the detection of most of the asymptomatic pediatric cases that otherwise would not have been diagnosed [12]. However, whether this risk for MIS-C is sustained with new SARS-CoV-2 variants and vaccination remains unknown.

In this study, we analyzed a large cohort of all consecutive MIS-C cases treated in Catalonia, Spain, since the onset of the pandemic, thanks to the effort of the multidisciplinary COPEDI-CAT network team. We aimed not only to estimate the main MIS-C epidemiological characteristics, but also to describe the clinical and laboratory findings, the type and the responses to the treatment administered and the final outcomes of the disease across the different SARS-CoV-2 variant epidemic waves.

Study design and study population

This is a multicenter ambispective observational cohort study of patients aged <18 years old in Catalonia, Spain, diagnosed with MIS-C during the period from April 20, 2020 to April 30, 2022. The WHO definition criteria were used for the inclusion of the cases [3].

Data sources and data analysis

Epidemiological and clinical data were obtained from the COVID-19 Catalan surveillance system and medical records of all hospitals in Catalonia included in the COPEDI-CAT project. Demographic, laboratory and clinical data were collected from hospital patient history and uploaded to the REDCap® database. Laboratory and clinical parameters were adjusted using age-specific normal ranges and collected at admission. Phenotype, severity and incidence of MIS-C were compared in different periods, regarding predominant variants (>50% of random samples) in our location (Wild type April 2020-February 2021 [13], Alpha February 2021-June 2021 [14], Delta June 2021-December 2021 [15], and Omicron December 2021-April 2022). In addition, we used the six epidemiological periods (based on successive waves, independently of variants) defined by the Spanish Public Health authorities to study the evolution of the MIS-C cases with regard to COVID-19 incidence [16]. MIS-C was divided by age groups in regard to vaccination recommendations (0-5 years, 6-11 years, 12-17 years). Vaccination status was verified through searches of national immunization information systems, including children vaccine cards. Patients were considered unvaccinated if they had received no doses, partially vaccinated if they had received one dose or completely vaccinated if they had received two doses (the second dose >14 days before the MIS-C episode) or one dose with previously documented SARS-CoV-2 infection.

MIS-C incidence per SARS-CoV-2 infection

We estimated the monthly MIS-C incidence rate per 1,000,000 people in all variant-associated periods by dividing the number of reported MIS-C cases in a month by the number of people <18 years old. In addition, we also calculated the rate between MIS-C cases and COVID-19 cases (from -30 days w.r.t. the MIS-C interval[2]) in each epidemiological wave and variant-associated period, since MIS-C cases are related to SARS-CoV-2 infections and its incidence cannot be considered separately from that of COVID-19. The public health authorities in Catalonia launched a protocol in September 2020 for testing all the exposed children within bubble groups in the schools (contacts of the initial case at school) [11,12], which was maintained until the end of January 2022, when Omicron was the prevalent variant. All the health districts or regions in Catalonia followed the same protocol, the diagnostic effort in the pediatric population was maintained everywhere throughout the pandemic, and the schools remained open between September 2020 till the end of the study-period. Vaccination status was registered individually for MIS-C, and data for SARS-CoV-2 vaccination for each age group was obtained by national COVID-19 surveillance.

Statistical analyses

We analyzed MIS-C cases during the pandemic, according to the different SARS-CoV-2 predominant variants. Demographics, clinical findings and phenotypes concerning organ involvement, hypotension and need for treatment in the intensive care unit, laboratory characteristics and specific treatment were included in the predominant variant related analysis. Statistical analyses were performed with R(v4.2.0) and Python(v3.7.13). Quantitative variables were presented as median and IQR, and categorical variables as the number of children for each category and the corresponding percentage. Fisher’s exact tests were used to compare categorical variables between groups, except for analyzing MIS-C monthly incidence and rate, where z-tests were performed. The Kruskal–Wallis test was used to compare groups for quantitative variables. A Benjamini & Hochberg correction was used for a more conservative measure of significance for multiple comparisons in results (excluding MIS-C rate and monthly incidence). The Alpha period was excluded from most analyses due to the low data volume, and the Wuhan period previous to July 1, 2020 was excluded from the MIS-C rate analyses because of the low testing capacity at that time. RR and its 95% CI were computed to compare rates of MIS-C and SARS-CoV-2 infections between variant periods. For all tests, results were considered significant if p< 0.05.

Epidemiology data

One-hundred fifty-two children were recruited, corresponding to the whole number of MIS-C cases during this study-period. Regarding the SARS-CoV-2 variant periods, 73, 5, 44, and 30 cases were diagnosed for Wuhan, Alpha, Delta, and Omicron periods, respectively (Table 1).

Demographic data

Median [IQR] age was 8 [4-11] years, 62.5% were male and 80.2% did not have any comorbidity. COVID-19 was previously diagnosed in 45.4% (69/152), mostly asymptomatic. Nearly 60% (91/152) were Caucasian, 15% (23/152) Hispanic from Latin-American countries, and 8.6% (13/152) Black African, among other ethnicities (Table 2). None of them died.

Laboratory evidence of SARS-CoV-2 data

In Figure 1, we describe the cohort of children regarding results for serological and microbiological tests for SARS-CoV-2 and vaccination against COVID-19. The median [IQR] between SARS-CoV-2 infection and MIS-C diagnosis was 5.1 [4.2-6.3] weeks. Overall, 86.2% (131/152) tested positive by SARS-CoV-2 IgG, 33 (21.7%) tested positive by SARS-CoV-2 RT-PCR, and 5 (3.3%) by rapid antigen test (Figure 1).

Clinical presentation at admission

Fever was the main clinical finding (150/152, 98.7%), for a median [IQR] of 4 [3-6] days before the MIS-C diagnosis, and 81.6% had >39^oC. Gastrointestinal symptoms (88.2%), and rash or skin lesions (59.2%) were, among others, the most common clinical findings, 81 (53.3%) had signs of shock, and 68 (44.7%) were admitted to an intensive care unit (Table 2).

Laboratory and echocardiography findings

Thrombocytopenia (<150x10⁹/L) was observed in 92 (60.5%) and lymphopenia (<1.0x10⁹/L) in 75 (49.3%) cases. Acute phase reactants were markedly elevated for all the patients, as well as the procoagulant biomarkers (Table 2). ALT was normal in 91 (59.9%), and elevated >250 UI/L only in four children. More than a half, 81 (53.3%), showed clinical features of cardiovascular compromise. Elevated Pro-BNP were >2000pg/mL in 65 (42.8%). Echocardiography was abnormal in 60 children (39.5%), 22 with ventricular dysfunction (14.5%), and 11 with coronary aneurysm (7.2%).

Treatment and Early Treatment Response

Specific treatments administered to the MIS-C cases are described in Table 3. Most of them (147/152, 96.7%) received immune modulating treatment (5.5% only IGIV, 12.3% only steroids and 82.2% combination of IGIV and steroids). Five patients did not receive specific treatment, corresponding at the beginning of the pandemic when protocols were not well defined. Only one patient with refractory MIS-C received treatment with a biologic agent anti-IL-1 (anakinra).

Vaccination and MIS-C

There were 60 (39.5%) vaccinated children against SARS-CoV-2, 42 with a single dose (5 before the MIS-C episode and 37 after it), and 18 fully-vaccinated (6 before the MIS-C episode and 12 after it) [Supplementary Information (SI)]. Exploring the cases vaccinated before the MIS-C episode to unrevealing any link with its occurrence, 8/11 (72.7%) received the vaccine <12 weeks before [Supplementary Information (SI)].

Estimated monthly MIS-C incidence per 1,000,000 people

The total population <18 years old in Catalonia is 1,361,915. From the beginning of the pandemic until April 30, 2022, mean monthly MIS-C incidence was 4.1 cases per 1,000,000 people (95%CI: 3.5-4.7). Monthly incidence was significantly lower in females throughout the study period (p= 0.006). Additionally, incidence was significantly higher for children aged 0 to 4 and 5 to 11 years (5.0 and 4.9 per 1,000,000 people, respectively) (Figure 2 and Table 1), than for adolescents aged 12 to 17 years (2.6 per 1,000,000) in all the possible combinations.

MIS-C rate per 1,000,000 SARS-CoV-2 infections

During the study-period there were 555,848 diagnosed SARS-CoV-2 infections, and 273 (95%CI: 230-316) MIS-C cases per 1,000,000 SARS-CoV-2 infections, with no statistically significant difference between males and females, except for the Omicron period (p= 0.02) (Table 1). The MIS-C rate per 1,000,000 SARS-CoV-2 infections was higher among children aged 0 to 4 years (456, 95%CI: 336-619) than 5 to 11 years (305, 95%CI: 243-383), and children aged 12 to 17 years (166, 95%CI: 120-228) (Table 1), with significant differences between children aged 0 to 4 and 5 to 11 (p= 0.048), 0 to 4 and 12 to 17 (p< 0.001), and 5 to 11 and 12 to 17 (p= 0.003) (Table 1).

Compared incidence and rates of MIS-C between different variants and waves

No significant differences of monthly MIS-C incidence per 1,000,000 people <18 years old were observed between the variant periods (p= 0.68). We did not include the Alpha period in this analysis due to the very low number of cases (n= 5) compared to other periods (Table 1). When comparing the rate ratios between periods, there was a significantly lower rate of MIS-C per SARS-CoV-2 infections during the Omicron period than during the Wuhan or Delta periods, for all the age groups and sex (Table 1). Figures 3a and 3b show the MIS-C rate throughout the different waves, by sex and age groups. The 95%CI confirm the significant differences of the sixth wave, mostly corresponding to the Omicron period, with regards to the second, third and fifth waves. The first and fourth pandemic waves cannot be included in this analysis due to the lack of diagnostic tests and very low MIS-C incidence, respectively.

In Table 2, the clinical characteristics of the MIS-C cases are shown for the variant periods. Regardless of the type of variant, the patients had similar phenotypes concerning organ involvement, hypotension and need for treatment in intensive care units, and length of hospital stay (p> 0.05). There was no significant difference in the type or combination of the treatment administered for MIS-C in the SARS-CoV-2 variant periods (Table 3).

We diagnosed 152 MIS-C cases among 1,361,915 children under 18 years of age in Catalonia, giving a monthly MIS-C incidence of 4.1 cases per 1,000,000 people (95%CI: 3.5-4.7), confirming that MIS-C is a very rare complication of SARS-CoV-2 infection among this population. This incidence is higher than that reported in Liguria, Italy [17], but very similar to other studies in the US [18] and Sweden [19]. It was significantly lower in females and adolescents (12-17years old), even before the start of vaccination in this age-group, but no differences were observed across the SARS-CoV-2 variant periods.

As the incidence of MIS-C among a specific population is determined by the number of SARS-CoV-2 infections that occurred 2-6 weeks before, we analyzed the incidence rate for MIS-C among the previously diagnosed SARS-CoV-2 infections. Although this variable is affected by the infection diagnostic capacity, the sustained surveillance protocols in the schools, with systematic screening of all classmates each time a positive case was detected, guaranteed a sustained diagnostic effort among the pediatric population between September 2020 and January 2022 [11, 12]. Omicron showed the significantly lowest rate, with a low MIS-C incidence when compared to the high number of infected children in all the age-groups. Moreover, the diagnostic effort was lower after the end of January 2022 because of the relaxation in the surveillance and quarantine measures in the schools [Supplementary Information (SI)], as seen with the increase in the positivity rate, so the MIS-C rate during the Omicron period is likely overestimated because the denominator might be much higher than the reported. This would entail even higher RR in pre-Omicron variant periods than the ones we estimated (Table 1). Possible hypotheses to explain this shift in the MIS-C rate include the Omicron variant itself, the high-prevalence of SARS-CoV-2 infection among the general population after two years of pandemic, or the high percentage of people who were fully vaccinated against SARS-CoV-2, among other unknown factors. Regarding the variant factor, our results are in concordance with a South African study performed during the Omicron period [20], and with another study conducted in South East England [21]. However, a recent report from the CDC found that MIS-C cases continued to be an important complication of SARS-CoV-2 infection during the last variant-periods [22].

Our current understanding of the immunopathology of SARS-CoV-2 and MIS-C is growing, but still limited. COVID-19 mRNA vaccine immunogenicity and effectiveness are well established in adolescents, and the preventive effect of vaccination on the incidence of MIS-C has been already described [23, 24]. A recent population-based cohort study in Denmark demonstrated the effectiveness of COVID-19 vaccination in preventing this disease during the Delta and Omicron period [25]. On the other hand, very few MIS-C cases have been reported following COVID-19 vaccination [26]. Therefore, the optimal SARS-CoV-2 vaccine strategy for patients with a history of MIS-C remains unclear, as demonstrated in a recent survey conducted by pediatricians from different countries [27]. In our study, only eight patients had been vaccinated against COVID-19 in the previous 12 weeks before the MIS-C episode, three fully-vaccinated and five after receiving the first vaccine dose [Supplementary Information (SI)], compared with 102 unvaccinated MIS-C cases that were eligible for vaccination due to their age. None of the vaccinated differed from the unvaccinated regarding the associated risk factors for severity. On the other hand, our study includes 49 children vaccinated against COVID-19, 37 with a single dose and 12 fully-vaccinated, after the MIS-C episode. None of them had a relapse of MIS-C after vaccination.

In our cohort, most of the children were Caucasian (60%), and Black African ethnicity represented 8.6% of the MIS-C cases. The proportion of immigrant people living in Catalonia [28] (year 2021) from geographic areas where the Black African population is prevalent is about 1.3%, much less than the percentage of MIS-C cases we had in our cohort for this ethnicity. This is in concordance with previous reports from Europe [29] and the US [18], suggesting an increased susceptibility of this population to present MIS-C after COVID-19.

Common presenting symptoms in our cohort were similar to those previously reported. We did not find any significant differences in clinical manifestations and laboratory data throughout the pandemic (Table 2 and SI), compared to the decrease of severity observed during the Omicron period in Israel [30].

We treated our patients with a combination of IVIG and steroids, with no significant difference in the treatment of MIS-C throughout the variant periods. We want to highlight the absence of mortality in our cohort. More studies are needed to understand if this combination therapy is needed after the era of vaccination.

Our study has some limitations, this was an exploratory analysis with multiple comparisons and small numbers of patients in the Alpha wave, thus the results should be interpreted cautiously. Appropriate incidence and rate estimations involve careful estimation of the numerator (MIS-C cases) and denominator (population and number of SARS-CoV-2 infections). These analyses are strengthened by MIS-C reporting through enhanced surveillance reporting across jurisdictions and time, because of the collaboration between primary care and hospital teams backing the project COPEDI-CAT. Unfortunately, we lacked information regarding the SARS-CoV-2 variant that caused each MIS-C episode, which could affect the variant period assignment of those cases that occurred during variant substitution processes. Nevertheless, all variants achieved prevalence rates higher than 90%, which supports the appropriate classification of most episodes. In addition, the analysis per epidemiological wave confirms the variant-related findings.

Our study analyzed monthly MIS-C incidence across different SARS-CoV-2 variant-periods, recruiting all the MIS-C cases, and being the first to compare the clinical presentation and organ involvement during different variant-periods, before and after vaccination status in children. We estimated a lower MIS-C rate per SARS-CoV-2 infection for all age-groups, including those not vaccinated, during the Omicron period. Regardless of variant type, the patients had similar phenotypes concerning severity and type of treatment. Knowledge of the MIS-C incidence, clinical presentation and severity following different SARS-CoV-2 variants is crucial for estimating MIS-C hospitalizations with new variants and in the debate on COVID-19 vaccination of children.

ALT- Alanine aminotransferase

CDC- Centers for Disease Control and Prevention

CI- Confidence Interval

COPEDI-CAT- Pediatric COVID-19 research network in Catalonia

COVID-19- Coronavirus Disease 2019

IL-1- interleukin-1

IQR- Interquartile range

IVIG- intravenous immunoglobulin

KD- Kawasaki disease

L- Liter

MIS-C- Multisystem Inflammatory Syndrome in Children

p- p-value for statistical significance

pg/ml- picograms per mililiter

Pro-BNP- N-terminal prohormone of brain natriuretic peptide

REDCap©- Research Electronic Data Capture

RR- Rate Ratio

RT-PCR- reverse transcriptase polymerase chain reaction

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

UI/L- International Units per liter

UK- United Kingdom

US- United States

WHO- World Health Organization

w.r.t. – With regard to

Acknowledgments

To all the COPEDI-CAT researchers for their great and tireless work through the pandemic, and to Spider’s Web translation website, and especially to Cristina Roman and Jane Perkins for their English style review of the manuscript.

Funding: This study has received funding for the data analysis from the “Fundació la Marató TV3” with file number 202134-30-31.

Competing interests: The authors have no relevant financial or non-financial interests to disclose.

Author contributions: This is a multidisciplinary study with contribution form pediatricians collecting data of their patients, biophysics exploring and analyzing the data, and epidemiologists interpreting and putting the data in context. Conceptualization, R.P., F.P., C.P., and A.S-A, funding acquisition, C.P. and A.S-A., investigation, data collection, and resources, all authors, methodology, data curation and data analysis, R.P., J.M.A., C.P., A.P., E.C., F.F., and A.S-A., writing-original draft preparation, R.P., C.P., J.M.A., and A-S-A., writing-review and editing, all authors, visualization, all the authors, supervision, R.P., C.P., and A-S-A. All authors have read and agreed to the published version of the manuscript.

Ethics approval: The study was reviewed and approved by the research ethics committee of the coordinating center (PR(AMI)271/2021). All the participating sites obtained their approval from the respective ethics committees for the collection of data related to the MIS-C cases. This research was based on the agreement established in Regulation 2016/679 of the European Parliament and the Council of Europe of April 27, 2016 on Data Protection, and Organic Law 3/2018 of December 5 on the Protection of Personal Data and the Guarantee of Digital Rights.

Consent to participate: Informed consent was obtained from all individual participants included in the study.

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Table 1. MIS-C cases (n=152), SARS-CoV-2 infections, MIS-C incidence and rate between MIS-C cases and SARS-CoV-2 infections (from -30 days w.r.t. the MIS-C interval) by SARS-CoV-2 variant. Population references (by group) for incidences are constant throughout all variants.

INCIDENCES PER VARIANTS
		Whole study period	Wuhan period (pre-Jul 1)	Wuhan period (post-Jul 1)	Alpha period	Delta period	Omicron period	P-val
MIS-C cases n(%)	Total	152 (100)	16 (100)	57 (100)	5 (100)	44 (100)	30 (100)	-
	0-4	41 (27·0)	6 (37·5)	16 (28·1)	3 (60·0)	9 (20·4)	7 (23·3)	-
	5-11	74 (48·7)	6 (37·5)	25 (43·8)	1 (20·0)	27 (61·4)	15 (50·0)	-
	12-17	37 (24·3)	4 (25·0)	16 (28·1)	1 (20·0)	8 (18·2)	8 (23·7)	-
	Female	57 (37·5)	6 (37·5)	21 (36·8)	4 (80·0)	18 (40·9)	8 (23·7)	-
	Male	95 (62·5)	10 (62·5)	36 (63·2)	1 (20·0)	26 (59·1)	22 (73·3)	-
SARS-CoV-2 infections	Total	555848 (100)	654 (100)	78158 (100)	28812 (100)	81814 (100)	366410 (100)	-
	0-4	89883 (16·2)	173 (26·5)	12674 (16·2)	4226 (14·7)	11388 (13·9)	61422 (16·8)	-
	5-11	242430 (40·2)	189 (28·9)	28905 (46·8)	11019 (47·1)	35934 (42·2)	166383 (37·8)	-
	12-17	223535 (43·6)	292 (44·6)	36579 (37·0)	13567 (38·2)	34492 (43·9)	138605 (45·4)	-
	Female	272806 (49·1)	339 (51·8)	38355 (49·1)	13877 (48·2)	41175 (50·3)	179060 (48·9)	-
	Male	283042 (50·9)	315 (48·2)	39803 (50·9)	14935 (51·8)	40639 (49·7)	187350 (51·1)	-
MIS-C monthly incidence (x10⁶)	Total	4·1	3·6	5·0	0·8	4·9	4·6	0·68^a
	0-4	5·0	6·1	6·4	2·3	4·6	4·8	0·85^a
	5-11	4·9	3·3	5·5	0·4	7·5	5·7	0·28^a
	12-17	2·6	2·4	3·7	0·4	2·4	3·2	0·7^a
	Female	3·1	2·8	3·8	1·4	4·1	2·5	0·6^a
	Male	4·9	4·3	6·1	0·3	5·6	6·5	0·73^a
Rate between MIS-C cases and SARS-CoV-2 infections (x10⁶)	Total	273	24465^S	729	174	538	82	<0·001^b
	0-4	456	34682^S	1262	710	790	114	<0·001^b
	5-11	305	31746^S	865	91	751	90	<0·001^b
	12-17	166	13699^S	437	74	232	58	<0·001^b
	Female	209	17699^S	548	288	437	45	<0·001^b
	Male	336	31746^S	905	67	640	117	<0·001^b
Rate ratio (Omicron reference)	Total	-	*	8·9 (5·7-13·8)	2·1 (0·8-5·5)	6·6 (4·1-10·4)	1	-
	0-4	-	*	11·1 (4·6-26·9)	6·2 (1·6-24·1)	6·9 (2·6-18·6)	1	-
	5-11	-	*	9·6 (5·1-18·2)	1·0 (0·1-7·6)	8·3 (4·4-15·7)	1	-
	12-17	-	*	7·6 (3·2-17·7)	1·3 (0·2-10·2)	4·0 (1·5-10·7)	1	-
	Female	-	*	12·2 (5·4-27·7)	6·5 (1·9-21·4)	9·8 (4·3-22·5)	1	-
	Male	-	*	7·7 (4·5-13·1)	0·6 (0·1-4·2)	5·4 (3·1-9·6)	1	-

^aP-values come from two-sided z-tests (α=0·05) excluding the Alpha period.

^bP-values come from two-sided z-tests (α=0·05) excluding the Wuhan period (before July 1, 2020).

*Rate ratio is not included for the Wuhan period before July 1, 2020, due to the lack of methods available for COVID-19 diagnosis elsewhere in Catalonia, Spain.

^SThe values of the MIS-C rate in Wuhan before July 1, 2020, are unable to be compared with the values for other periods (Wuhan after July 1, 2020, Alfa, Delta and Omicron) due to the lack of access to COVID-19 diagnosis in the former period. Therefore, the analysis comparing the rates across the variants does not include the period of Wuhan before July 1, 2020.

Table 2. MIS-C bivariable analysis for epidemiological, clinical, laboratory, echocardiography, and hospital outcomes according to SARS-CoV-2 variant periods.

	All MIS-C n: 152, 100%	Wuhan period n: 73, 48%	Alpha period n: 5, 3%	Delta period n: 44, 29%	Omicron period n: 30, 20%	P-val^a
Rate (x10⁶)^b	273	926	173	538	82	<0·001
Monthly Incidence (x10⁶)	4·1	4·6	0·8	4·9	4·6	<0·001
Demographic and COVID-19 related findings
Gender n(%)
Male Female	95 (62·5) 57 (37·5)	46 (63·0) 27 (37·0)	1 (20·0) 4 (80·0)	26 (59·1) 18 (40·9)	22 (73·3) 8 (26·7)	0·83 -
Age (years) median(IQR)	8 (4-11)	8 (4-12)	4 (2-5)	8 (5-10)	8 (5·25-11·75)	0·87
Ethnicity/race n(%)
Caucasian Hispanic (Latin America) Black African Arabic Asian Other/mixed	91 (59·9) 23 (15·1) 13 (8·6) 12 (7·9) 7 (4·6) 6 (4·0)	48 (65·8) 8 (11·0) 8 (11·0) 3 (4·1) 3 (4·1) 3 (4·1)	2 (40·0) 1 (20·0) 1 (20·0) 0 (0·0) 1 (20·0) 0 (0·0)	20 (45·5) 10 (22·7) 3 (6·8) 7 (15·9) 1 (2·3) 3 (6·8)	21 (70·0) 4 (13·3) 1 (3·3) 2 (6·7) 2 (6·7) 0 (0·0)	0·47 0·69 0·83 0·47 1 0·83
Recent COVID-19 infection n(%)	69 (45·4)	29 (42·7)	2 (40·0)	23 (52·3)	15 (50·0)	0·83
SARS-CoV-2 at MIS-C diagnosis n(%)
RT-PCR positive RAT positive	33 (21·7) 5 (3·3)	19 (26·0) 0 (0·0)	2 (40·0) 0 (0·0)	8 (18·2) 1 (2·3)	4 (13·3) 4 (13·3)	0·47 0·13
IgG SARS-CoV-2 positive at MIS-C diagnosis n(%)	131 (86·2)	64 (87·7)	3 (60·0)	41 (93·2)	23 (76·7)	0·47
Clinical findings (n(%))
Fever	150 (98·7)	71 (97·3)	5 (100·0)	44 (100·0)	30 (100·0)	1
Fever (>39)	124 (81·6)	57 (78·1)	5 (100·0)	36 (81·8)	26 (86·7)	1
Rash	90 (59·2)	42 (58·3)	4 (80·0)	25 (56·8)	19 (63·3)	1
Conjunctivitis	83 (54·6)	33 (45·2)	4 (80·0)	22 (50·0)	24 (80·0)	0·13
Oral mucosa lesions	55 (36·2)	25 (34·3)	1 (20·0)	13 (29·6)	16 (53·3)	0·47
Cervical lymphadenopathy (> 1.5 cm)	29 (19·1)	11 (15·1)	0 (0·0)	11 (25·0)	7 (23·3)	0·79
Gastrointestinal symptoms	134 (88·2)	65 (89·0)	2 (40·0)	39 (88·6)	28 (93·3)	1
Respiratory symptoms	35 (23·0)	16 (21·9)	1 (20·0)	11 (25·0)	7 (23·3)	1
Neurologic symptoms	19 (12·5)	11 (15·1)	0 (0·0)	8 (18·2)	1 (3·3)	0·66
Hypotension/shock	81 (53·3)	42 (57·5)	0 (0·0)	23 (52·3)	16 (53·3)	1
ICU admission	68 (44·7)	36 (49·3)	0 (0·0)	19 (43·2)	13 (43·3)	1
Laboratory results
Hemoglobin (g/dL) median (IQR)	11·8 (10·9-12·7)	12 (11·0-12·6)	11·1 (10·7-11·9)	11·4 (10·8-12·0)	12·5 (11·1-12·9)	0·69
Leukocytes (10⁹/L) median (IQR)	9·45 (6·35-13·00)	9·55 (6·4-13·3)	9·8 (7·7-10·93)	8·19 (5·64-11·4)	9·55 (6·4-13·3)	0·47
Platelets (10⁹/L) median (IQR)	171 (114-232·25)	162 (110-230)	327 (211-330)	170·5 (132·5-227·5)	167 (103·5-229)	0·47
Platelets < 150 (10⁹/L) n(%)	92 (60·5)	30 (41·1)	0 (0·0)	17 (38·6)	13 (43·3)	1
Lymphocytes < 1.0 (10⁹/L) n(%)	75 (49·3)	37 (50·7)	2 (40·0)	22 (50·0)	16 (53·3)	1
CPR (mg/dL) median(IQR)	17·25 (11·28-24·82)	17·2 (10·73-25·7)	21·8 (15·9-23·39)	16·5 (12·55-22·36)	17·75 ( 10·95-25·57)	1
Procalcitonin (ng/mL) median(IQR)	3·7 (1·43-10·67)	3·67 (1·45-7·43)	3·16 (2·25-4·07)	2·46 (1·24-6·48	7·0 (2·6-17·45)	0·78
Ferritin (ng/mL) median(IQR)	399 (237-640)	393 (193·5-569·5)	547 (496·25-592·92)	350 (240·0-575·25)	631·5 (332·75-1460·25)	0·47
IL-6 (ng/L) median(IQR)	162·29 (52-380·9)	100·6 (31·37-248·52)	308 (275·45-387·35)	182·55 (92·27-385·17)	206·75 ( 82·75-392·17)	0·67
Pro-BNP (pg/mL) median (IQR)	2411·0 (583·1-5804·5)	3277·0 (1006·0- 7726·5)	1093·0 (306·475-2212·5)	1401·5 (301·5-4132·0)	2230·5 (675·5-10049·7)	0·47
D-dimer (ng/mL) median(IQR)	2150·5 (1187·75-4192·5)	1999 (854-5030)	1719 (1624-1857·5)	2652 (1487·5-3948·5)	2039 (1630-5130)	0·96
ALT (IU/L) n(%)
<50 >250	91 (59·9) 4 (2·6)	42 (57·5) 3 (4·1)	1 (20·0) 1 (20·0)	32 (72·7) 0 (0·0)	16 (53·3) 0 (0·0)	0·76 0·96
Echocardiography
Pathologic echocardiography	60 (39·5)	31 (42·5)	2 (40·0)	16 (36·4)	11 (36·7)	0·96
Ventricular dysfunction	22 (14·5)	12 (16·4)	0 (0·0)	6 (13·6)	4 (13·3)	0·83
Coronary abnormalities	15 (9·8)	9 (12·3)	0	4 (9·1)	2 (6·7)	0·96
Hospital stay
Length of hospital stay (days) median(IQR)	7 (5-9)	7 (5-10·25)	6 (5-9)	7 (5-8)	5 (4-8)	0·75
PICU admission n(%)	68 (44·7)	36 (49·3)	0 (0·0)	19 (43·2)	13 (43·3)	1
Length of PICU stay (days) median(IQR)	4 (2-5)	5 (3-5·25)	-	3 (2-5)	3 (2-5)	0·67

The periods were Wild-type variant April 2020-December 2020, Alfa variant January 2021-July 2021, Delta variant July 2021-December 2021, Omicron variant December 21-February 2022.

Abbreviations: ECMO, extracorporeal membrane oxygenation, ICU, intensive care unit, IL-6, interleukin 6, IQR, interquartile range, MIS-C, multisystem inflammatory syndrome in children, NT-proBNP, N-terminal pro b-type natriuretic peptide, RT-PCR, reverse transcription polymerase chain reaction, RAT: rapid antigen test, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^aP-values (α=0·05) come from Kruskal-Wallis tests in the case of quantitative variables and Fisher’s exact tests in the case of categorical variables (except for MIS-C rate and incidence, where z-tests were performed). The Alpha period has been excluded from all tests except from MIS-C rate. P-values reported, except for MIS-C Rate and Incidence, have been adjusted, together for Tables 2 and 3, using the Benjamini & Hochberg method, to account for multi-testing.

^bFor the analysis of the rate between MIS-C cases and COVID-19 cases across SARS-CoV-2 variants, the Wuhan period is excluded for the calculation of the P-value due to the lack of COVID-19 diagnosis occurring in the first pandemic wave (no access to diagnosis methods such as RT-PCR or RAT). This leads to a bias for the estimation of the ratio (overestimated) in this period.

Table 3. Bivariable analysis of the treatment of MIS-C cases according to SARS-CoV-2 variant periods.

Characteristics	All MIS-C	Wuhan period	Alpha period	Delta period	Omicron period	P-val
Immunomodulation treatment^a	146	67	5	44	30	0·39
Only IGIV (n=8)	8 (5·5)	6 (9·0)	0 (0·0)	1 (2·3)	1 (3·3)	0·76
Only steroids (n=18)	18 (12·3)	7 (10·4)	1 (20·0)	7 (15·9)	3 (10·0)	0·86
IGIV and steroids (n=120)	120 (82·2)	54 (80·6)	4 (80·0)	36 (81·8)	26 (86·7)	0·71
First IGIV (n=13)^b At same time (n=88)^b First steroids (n=11)^b Unknown order (n=8)^b	13 (10·8) 88 (73·3) 11 (9·2) 8 (6·7)	7 (13·0) 37 (68·5) 6 (11·1) 4 (7·4)	1 (25·0) 3 (75·0) 0 (0·0) 0 (0·0)	2 (5·6) 27 (75·0) 3 (8·3) 4 (11·1)	3 (11·5) 21 (80·8) 2 (7·7) 0 (0·0)	0·96 0·67 1 0·7
Steroids (days of treatment) median[IQR]	11 [4-22]	19 [4-25]	4 [3·5-16·5]	6.5 [4-17]	9 [5-13]	1
Anakinra (n=1)	1 (0·7)	1 (0·7)	0	0	0	1
Supportive Treatment^c(MIS-C cases)	152	73	5	44	30	1
Oxygen treatment ECMO IMV NIV	7 (4·6) 1 (0·7) 3 (2·0) 3 (2·0)	5 (6·8) 1 (1·4) 2 (2·7) 2 (2·7)	0 0 0 0	2 (4·6) 0 1 (2·3) 1 (2·3)	0 0 0 0	0·83 1 1 1
Extrarenal purification	2 (1·3)	1 (1·4)	0	0	1 (3·3)	0·83
Inotropic	48 (31·6)	24 (32·9)	0	14 (31·8)	10 (33·3)	1
Antibiotics	124 (81·6)	59 (80·8)	5 (100)	36 (81·8)	24 (80·0)	1
Other treatments^d	40	24	0	13	3	0·47

^aTotal number of cases (n) refers to all the cases for which steroids, IGIV or both of them were administered.

^bPercentages for subcategories refer to the number of cases receiving IGIV and/or steroids.

^cTotal number of cases (n) refers to all MIS-C cases included in the study.

^dOther treatments include: AAS (n=29), enoxaparin (n=11), hydroxychloroquine (n=2), remdesivir (n=1), insulin (n=1), vitamin K (n=1)

No competing interests reported.

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Multisystem Inflammatory Syndrome in Children and SARS-CoV-2 variants: a two-year ambispective multicentric cohort study in Catalonia, Spain.

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