AbstractObjectives

: Multisystem Inflammatory Syndrome in Children (MIS-C) is the result of an immune response triggered by a prior exposure to the SARS-CoV-2. The clinical presentation of MIS-C overlaps with other life-threatening bacterial infections, in which antimicrobials are the mainstay therapy. The aim of study was to describe the use of antibiotics in children with MIS-C in Poland.

Methods

: The analysis of 345 children reported from 42 Polish cities to the national MultiOrgan Inflammatory Syndromes COVID-19 Related Study (MOIS-CoR Study) from June 2020 to April 2021.

Results

: At least one antibiotic was used in 310 (90%) children, mainly third-generation cephalosporin (251/310). Broad-spectrum antibiotics were used in 258 (75%) children and 224 (87%) received this treatment for more than three days. Concentrations of serum procalcitonin >2µg/L and presence of lower respiratory symptoms were associated with increased odds of receiving any antibiotic.

Conclusions

: Although bacterial infections in MIS-C patients are uncommon, we show that MIS-C poses a challenge to clinicians faced with the decision to start, continue, or stop antimicrobial therapy. Antibiotic stewardship in MIS-C patients should be improved to ensure that likely pathogens are treated and that antimicrobials are stopped when bacterial infections are excluded and the diagnosis of MIS-C is made.

Keywords

Background

Since April 2020, after the first wave of the coronavirus disease 2019 (COVID-19) pandemic, many reports have documented a new hyperinflammatory condition in children manifesting with a persistent fever, fatigue, and a variety of symptoms, including multiorgan involvement and elevated inflammatory markers (Verdoni et al. 2020, Belot et al. 2020, Davies et al. 2020). The first definition of Pediatric Inflammatory Multisystem Syndrome Temporally Associated with COVID-19 (PIMS-TS) was announced by the Royal College of Pediatrics and Child Health (RCPCH) on 1 May (Health Policy Team, 2020). The alternative name for this disease proposed in the United States of America was Multisystem Inflammatory Syndrome in Children (MIS-C) and it was adopted by the World Health Organization (WHO)(CDC, 2020).

Since mid-May 2020, the CDC has been tracking case reports of MIS-C. According to the CDC, as of March 28, 2022 in the USA, the total number of MIS-C patients meeting the definition was 7880. The total number of children who had died due to MIS-C was 66. The median age of children with MIS-C was 9 years, with half of children with MIS-C being between the ages of 5 and 13 years; 60% of reported patients were male(CDC, 2022).

PIMS monitoring reports are also being conducted in Europe. Since May 25, 2020 Poland has been conducting nationwide surveillance of paediatric inflammatory syndromes in the MultiOrgan Inflammatory Syndromes COVID Related Study (MOIS-CoR)(Okarska-Napierała, 2020). Such monitoring enables the exchange of experiences between treatment centres and the development of common rules of conduct based on national and international experience.

Current evidence indicates that MIS-C is the result of an exaggerated innate and adaptive immune response, characterized by a cytokine storm, and that it is triggered by prior SARS-CoV-2 exposure. Pathogenically, it is associated with immune-mediated post-infectious hyperinflammation, involving fever, severe inflammation and multiorgan dysfunction leading to vasoplegic shock requiring vasopressor therapy. Cardiovascular involvement is apparently marked by acute myocardial injury/myocarditis and the development of coronary artery aneurysms(Mahase, 2020). A characteristic element is a significant increase in inflammatory markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, and ferritin. Therapy essentially consists of anti-inflammatory and immunomodulatory medications like intravenous immunoglobulins and steroids, based on the knowledge that the disorder is induced by post-infectious immune dysregulation(Henderson et al., 2020). The course of the disease is characterized by a strong inflammatory reaction, which requires differentiation from a septic state, and many clinicians also implement empirical antibiotic therapy.

The aim of this study was to assess the frequency of, clinical reasons for and type of antibiotics prescribed in children with MIS-C.

Methods

Patient data

We analysed data from the Polish MOIS-CoR. Children aged 0–18 years with features of MIS-C from 42 cities in Poland were voluntarily reported. Anonymized patients’ data were collected through an online questionnaire developed for that purpose(10).

For the purpose of this study WHO MIS-C case definition criteria were adopted(WHO, 2022). The case definition included the following criteria: children aged 0–18 years with fever > 3 days AND two of the following: a) Rash or bilateral non-purulent conjunctivitis or signs of mucocutaneous inflammation (oral, hands or feet); b) Hypotension or shock; c) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities, including echocardiography (ECHO) findings or elevated Troponin/N-terminal (NT)-pro B-type natriuretic peptide (proBNP); d) Evidence of coagulopathy: by prothrombin time (PT), partial thromboplastin time (PTT), elevated d-Dimers; e) Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain) AND elevated markers of inflammation such as ESR, CRP, or procalcitonin AND no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes AND evidence of COVID-19: reverse transcription polymerase chain reaction (RT-PCR), antigen test or serology positive, or likely contact with patients with COVID-19. Cases not meeting the WHO criteria and cases with incomplete crucial data were excluded from the analysis.

Statistical methods

The summary statistics for continuous variables are presented as a median with interquartile range (IQR), and categorical variables are presented as frequencies. The continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared between groups using χ2 tests. Binary logit regression models were used to identify variables that were associated with the probability of using antibiotics in MIS-C patients. The results were considered statistically significant when the p-value was less than 0.05. The statistical analysis was conducted using TIBCO Software Inc. (2017) Statistica, version 13 (Palo Alto, CA, USA).

Ethical considerations

Ethical approval was obtained from the Bioethics Committee at Wroclaw Medical University (CWN UMW BW: 313/2020). A waiver of informed consent was obtained with only deidentified data transmitted and analysed.

Results

Among the 437 pediatric patients reported to MOIS-CoR with suspected MIS-C, 345 cases fulfilled the WHO criteria for MIS-C associated with SARS-CoV-2 and were eligible for study inclusion. All cases were registered between June 2020 and April 2021. The majority of children (n=293, 85%) were admitted over a 3-month period from November 2020 to January 2021 during the second COVID-19 wave in Poland. There were 214 boys and 131 girls in the study group. All children were of European white ethnicity, and the median age was 8.6 years (range 4 months – 17 years). There were nine children under the age of one, and 82 children aged between 1 and 5 years. Characteristics of the study group are shown in Table 1.

Table 1Characteristics of the study group

Continuous data are presented as medians with interquartile range, categorical data are presented as frequencies. Denominators lower than the sample size indicate missing data.

Use of antibiotics was common in the analysed group. A total of 310 (90%) children diagnosed with MIS-C were administered at least one antibiotic (Fig. 1). Forty-nine (14%) children received antibiotics from at least three different classes. The most commonly used antibiotics were third generation cephalosporins, being used in 48% of children who were treated with antibiotics.

Figure 1Use of antibiotics in children diagnosed with MIS-C in Poland, registered in the database, presented as the total number of different antibiotics used (A), and a percentage of children treated with a specific group of antibiotics (B). The total percentage in (B) does not sum up to 100% because children were treated with different combinations of listed antibiotics. Abbreviations: Abx, antibiotics; Cephalosporins-3G; third generation cephalosporins; Cephalosporins-1/2G, first and second generation cephalosporins

Overall, use of broad-spectrum antimicrobials (third generation cephalosporins, meropenem, vancomycin, aminoglycosides) in monotherapy or combination therapy was common. These antibiotics were administered to 258 (75%) of all children diagnosed with MIS-C. Of those 258, 224 (87%) children were treated with these regimens for more than 3 days, whereas 34 (13%) received that treatment for less than 3 days. Figure 2 shows that antimicrobial treatment did not change over time. Polish guidelines on the treatment of MIS-C were published in December 2020; however, this had no effect on the duration and type of antimicrobials used in these patients (Okarska-Napierała et al., 2021).

Figure 2Children registered in the database, hospitalized with pediatric inflammatory multisystem syndrome, divided by the type of antimicrobial treatment. The upper graphs shows the monthly number of cases. The lower stack area chart shows how antimicrobial treatments changed over time in relation to each other.

Compared to those who did not receive antimicrobials, children treated with antibiotics were characterised by higher concentrations of inflammatory markers and the presence of respiratory tract symptoms. Using a binary logit regression model, we aimed to identify variables that were associated with the risk of using antibiotics in MIS-C patients. In univariable analysis we found that children with signs of upper and lower respiratory tract infections were over twice as likely to receive any antibiotic (Fig. 3). Also, increased serum concentrations of CRP over 100 mg/L, and procalcitonin over 2 µg/L were associated with an increased risk of receiving antibiotics. Age, comorbidities, and treatment in an intensive care unit were not associated with the odds of using antibiotics in this study group. Importantly, however, all infants with MIS-C were given antimicrobial treatment. A multivariable analysis revealed that increased procalcitonin and signs of lower respiratory tract infection were the only two variables significantly associated with around 3-fold higher odds of using antibiotics in children with MIS-C.

Figure 3Binominal logistic regression analysis of variables associated with the risk of receiving antimicrobial treatment. The age-related risk was calculated with reference to age under one year. Abbreviations: CXR, chest X-ray; CT, computed tomography; PICU, pediatric intensive care unit; CRP, C-reactive protein

Discussion

Treatment of MIS-C involves an immunomodulatory approach, i.e. the application of an intravenous infusion of immunoglobulin, glucocorticosteroid and, in some specific cases, biological treatment, the use of acetylsalicylic acid to prevent an increased clotting tendency, as well as symptomatic treatment. Due to the complex clinical picture of MIS-C, which resembles the initial stadium of a serious bacterial infection such as sepsis, toxic shock syndrome, or bacterial intestinal infection, doctors must consider the use of broad-spectrum antibiotic therapy in the initial treatment (Harwood et al. 2021, McMurray et al. 2021, Gharby et al. 2016).

Paediatricians all over the world, including during the COVID-19 pandemic, have raised concerns about the numerous threats associated with the use of broad-spectrum antibiotics – from individual complications, such as adverse reactions and intestinal microbiota disorders, to the selection of antibiotic-resistant bacterial strains, which cause a particular problem in the hospital environment. There have been few studies analysing the irrelevant use of antibiotic therapy in children; however, the available data estimates that antibiotic therapy was used improperly in up to 20% of hospitalized paediatric patients (Gharby et al. 2016, Tan et al. 2020, Tribble et al 2020). The problem of inadequate antibiotic therapy is noticeable in both children and adults as early as in the treatment of SARS-CoV-2 infection itself. With respect to MIS-C treatment, antibiotic treatment should be terminated as soon as the MIS-C diagnosis is established or when negative results of the microbiological examination are obtained (Harwood et al. 2021).

A limited number of studies analysing the frequency of antibiotic application in MIS-C have been published to date, many of which analysed groups of patients with COVID-19 and those with MIS-C.

In a multicentre analysis comprising 990 children being treated for COVID-19 and MIS-C in seven hospitals in Latin America, it was stated that antibiotic therapy was used in 24.5% of children within the whole group (MIS-C was diagnosed in 7%, and was a significant factor increasing the use of antibiotics)(Yock-Corrales et al. 2021a). British authors associated with Paediatric Research Across the Midlands provided data from hospitals in the United Kingdom, which also showed a high percentage of antibiotic prescriptions for patients diagnosed with COVID-19 and MIS-C (antibiotics were used in 64% of children, almost half of whom were given broad-spectrum antibiotics, and in 84% of children diagnosed with MIS-C)(19). Significantly lower use of antibiotics was noted in Italian clinics, where an antibiotic was used in only 10 out of 117 children with COVID-19 or MIS-C; five of them were diagnosed with MIS-C, and one patient had sepsis(18). In a study of children diagnosed with PIMS-TS in the United Kingdom and Ireland, antibiotics were used in 92.9% (249/268) of children(Han et al. 2021).

It is noteworthy that, in previous years, the dilemma concerning the use of antibiotics in multisystem inflammatory syndrome was considered with respect to Kawasaki disease. In a study analysing 140 patients with Kawasaki disease, the prevalence of antibiotic therapy before establishing the diagnosis was estimated at 54.3%(Cattalini et al. 202120). In a study concerning the course and treatment of Kawasaki disease in comparison with that of MIS-C in Italy, it was stated that antibiotics were used in 72.7% of the entire analysed group, whereby the frequency of taking them in MIS-C was significantly higher than in Kawasaki disease (73.6% vs. 35.4%)(Flood et a. 2021). The difficulties in establishing the optimal initial treatment were also highlighted by the authors of a study carried out in one of the London hospitals. In this study, a group of experts made therapeutic decisions in the case of MIS-C suspicion. All patients received broad-spectrum antibiotics(Papadopoulou et al. 2021). The authors of a Turkish study, analysing the treatment of 20 children diagnosed with MISC-C who were hospitalized in Istanbul, also reported the use of empiric antibiotic therapy in all patients(Öcal et al. 2021).

The majority of the cited publications did not analyse the profile of antibiotics used in detail but concentrated on other aspects of MIS-C treatment. The authors of the cited studies stated that, given the concern over the increasing number of multidrug-resistant strains of bacteria, it is crucial to develop clear guidelines concerning the use of antibiotic therapy in both COVID-19 and MIS-C.

The above-mentioned reports are consistent with the results of our study describing the frequency of antibiotic use in Polish patients diagnosed with MIS-C. We have shown that the majority of children diagnosed with MIS-C were given antibiotic therapy in the course of their treatment. Third generation cephalosporins were the most commonly used antibiotics, followed by first and second generation cephalosporins, penicillin and macrolides, polypeptide antibiotics and others, and as many as 14% of children were given antibiotics from three different groups. Most of the treated children were given antibiotics for more than 3 days. The frequency of antibiotic application did not change significantly during the almost 12 months of data gathering, even after publishing and updating the Polish procedure guidelines for treating children with MIS-C(Okarska-Napierała et al. 2021). This observed high antibiotic use in a Polish children with MIS-C, in particular broad-spectrum antibiotics, is alarming.This observation is consistent with the reports of other authors and indicates the need to educate medical personnel about rational antibiotic therapy (Yock-Corrales et al. 2021b)

The publications we analysed as well as the data from our study indicate an urgent need to provide the most accurate diagnostic criteria for the identification of MIS-C and to promote them widely in order to avoid the prolonged use of broad-spectrum antibiotics in children with this complex disease entity. It seems that, due to the disease pattern and the similarity of symptoms to serious bacterial infections, it will be difficult to avoid antibiotic use in the initial phase of treatment. The emphasis should be placed on early withdrawal of antibiotics after the diagnosis is made. Databases run by expert assemblies in various countries and meta-analyses summarizing multiple studies as well as international cooperation may be particularly useful for optimization of treatment in the case of MIS-C.

Our study had some limitations. Due to the voluntary participation in the register the number of reported MIS-C cases might have been an underestimate or biased by non-random sampling. However, it is important to note a major strength of this study. We included data from across 42 Polish cities; hence, our study provides a good overview of clinical practices in the management of MIS-C patients throughout Poland.

Conclusions

Our study shows that multisystem inflammatory syndrome in children poses a challenge to clinicians faced with the decision to start, continue, or stop antimicrobial therapy. Signs of MIS-C overlap with other life-threatening conditions, in the majority of which antimicrobials are the mainstay therapy. Although bacterial infections in MIS-C patients are uncommon, proper antimicrobial stewardship is difficult, especially when inflammatory markers are significantly elevated or lower respiratory tract infection signs are present. These complex patients should be discussed with paediatric infectious disease or microbiology specialists to ensure that likely pathogens are treated and that antimicrobials are stopped when they are no longer necessary. Our study shows that multi-system inflammatory syndrome in children presents a challenge for clinicians who must make the decision to start, continue or stop antimicrobial therapy. The symptoms of MIS-C overlap with other life-threatening conditions, most of which antimicrobial drugs are the primary therapy. Although bacterial infections in patients with MIS-C are rare, proper management of antimicrobials is difficult, especially when markers of inflammation are markedly elevated or symptoms of a lower respiratory tract infection are present. These complex patients should be discussed with pediatric infectious diseases or microbiology specialists to ensure treatment of possible pathogens and the discontinuation of antimicrobials when no longer needed. It is of utmost importance that emergency pediatricians provide rational, empirical antibiotic therapy and endeavor to terminate it early upon confirmation of MIS-C.

Conflict of Interest: The authors declare no conflict of interest.

Funding Source: The authors received no specific funding for this work.

Ethical Approval statement: Ethical approval was obtained from the Bioethics Committee at Wroclaw Medical University (CWN UMW BW: 313/2020). A waiver of informed consent was obtained with only deidentified data transmitted and analysed.

References:

<BIBL>

Belot A, Antona D, Renolleau S, et al. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020. Eurosurveillance 2020;25:2001010.

Cattalini M, Della Paolera S, Zunica F, et al. Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey. Pediatr Rheumatol 2021;19:29–33.

Centers for Disease Control and Prevention (CDC). Available online: https://covid.cdc.gov/covid-data-tracker/#mis-national-surveillance (accessed on 08 April 2022).

Centers for Disease Control and Prevention (CDC). Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). CDC: Atlanta, GA, USA. Available online: https://www.cdc.gov/mis-c/hcp/ (accessed on 29 July 2020).

Davies P, Evans C, Kanthimathinathan HK, et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: A multicentre observational study. Lancet Child Adolesc Health 2020;4:669–77.

Flood J, Shingleton J, Bennet E, et al. Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): Prospective, national surveillance, United Kingdom and Ireland, 2020. Lancet Reg Health Eur 2021;3:100075.

Gharbi M, Doerholt K, Vergnano S, et al.; ARPEC project group members. Using a simple point-prevalence survey to define appropriate antibiotic prescribing in hospitalised children across the UK. BMJ Open 2016;3;6(11):e012675.

Han SB, Lee SY. Antibiotic use in children with Kawasaki disease. World J Pediatr 2018;14:621–622.

Harwood R, Allin B, Jones CE, et al. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health 2021;5(2):133–141.

Health Policy Team. Guidance—Paediatric Multisystem Inflammatory Syndrome Temporally Associated with COVID-19. Royal College of Paediatrics and Child Health: London, UK. Available online: https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19 (accessed on 29 July 2020).

Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2. Arthritis Rheumatol 2021;73(4):e13–e29.

Ludwikowska KM, Okarska-Napierała M, Dudek N, et al. Distinct characteristics of multisystem inflammatory syndrome in children in Poland. Sci Rep 2021;11(1):23562.

Mahase E. Covid-19: Cases of inflammatory syndrome in children surge after urgent alert. BMJ 2020;15:369.

McMurray JC, May JW, Cunningham MW, Jones OY. Multisystem Inflammatory Syndrome in Children (MIS-C), a post-viral myocarditis and systemic vasculitis – A critical review of its pathogenesis and treatment. Front Pediatr 2020;16;8:626182.

Öcal DS, Tosun Ö, Öztürk K, et al. SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C). A single center's experience [published online ahead of print, 2021 Apr 23]. Minerva Pediatr (Torino) 2021;10.23736/S2724-5276.21.06327-8.

Okarska-Napierała M, Ludwikowska K, Jackowska T, et al. Approach to a child with pediatric inflammatory multisystem syndrome with Covid-19. Przegl Ped 2021;50(2):1–11.

Okarska-Napierała M, Ludwikowska KM, Szenborn L, et al. MOIS CoR Study Group; Kuchar, E. Pediatric Inflammatory Multisystem Syndrome (PIMS) did occur in Poland during months with low COVID-19 prevalence, preliminary results of a nationwide register. J Clin Med 2020;9:3386.

Papadopoulou C, Al Obaidi M, Moraitis E, et al. Management of severe hyperinflammation in the COVID-19 era: the role of the rheumatologist. Rheumatology 2021;60;2:911–17.

Tan SH, Ng TM, Tay HL, et al. A point prevalence survey to assess antibiotic prescribing in patients hospitalized with confirmed and suspected coronavirus disease 2019 (COVID-19). J Glob Antimicrob Resist 2021;24:45–47.

Tribble AC, Lee BR, Flett KB, et al. Sharing antimicrobial reports for Pediatric Stewardship (SHARPS) Collaborative. Appropriateness of antibiotic prescribing in United States Children's Hospitals: A national point prevalence survey. Clin Infect Dis 2020;71(8):e226–e234.

Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study. Lancet 2020;395:1771–78.

WHO. Multisystem Inflammatory Syndrome in Children and Adolescents with COVID-19. Available online: https://www.who.int/publications-detail-redirect/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 (accessed on 8 April 2022).

Yock-Corrales A, Lenzi J, Ulloa-Gutiérrez R, et al. High rates of antibiotic prescriptions in children with COVID-19 or multisystem inflammatory syndrome: A multinational experience in 990 cases from Latin America. Acta Paediatr 2021;110:1902–1910.

Yock-Corrales A, Lenzi J, Brizuela M, et al. COVID-DOMINGO Study Group. Tackling antibiotic resistance during the COVID-19 pandemic is a new challenge for paediatricians. Acta Paediatr. 2021 Sep;110(9):2650-2651.

(1*)Collaborators: MOIS CoR Study Group: Marta Barszcz(4), Elżbieta Berdej-Szczot(10), Sebastian Brzuszkiewicz(11), Piotr Buda(12), Alicja Czajka(13), Agnieszka Czech(4), Ewa Czerwińska(4), Magdalena Figlerowicz(9), Małgorzata Firek-Pędras(10), Aneta Gawlik(10), Ewelina Gowin(14,15), Olga Izdebska(16), Danuta Januszkiewicz-Lewandowska(17), Justyna Kiepuszka(18), Agnieszka Koczwara(19), Danuta Koszałko(20), Magdalena Kośmider-Żurawska(21), Janusz Książyk(12), Beata Kucińska(22), Martyna Kukawska(23), Anita Lackowska(24), Katarzyna Łapacz(13), Agnieszka Maliszak(25), Anna Mania(9), Joanna Mańdziuk(5), Artur Mazur(3), Cezary Niszczota(22), Paulina Opalińska-Zielonka(26), Katarzyna Rojewska(18), Anna Rożnowska-Wójtowicz8, Bartosz Siewert(14, 15), Paulina Sobiczewska(27), Lidia Stopyra(28), Agnieszka Stroba-Żelek(29), Joanna Stryczyńska-Kazubska(14,15), Tomasz Szatkowski(3), Barbara Szczepańska(3), Maciej Szczukocki(3),Robert Szylo(29), Filip Tyc(30), Katarzyna Wielgos(31), Ewa Wołowska(24), Jacek Wysocki(14,15), Anna Zacharzewska(32), Marcin Zaniew(33), Marzena Zielińska(21), Katarzyna Zięba-Glonek(34)

10.Department of Paediatrics and Paediatric Endocrinology, Upper-Silesian Paediatric Health Center School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. 11. Provincial Specialist Children's Hospital Prof. S. Popowski in Olsztyn, ul. Żołnierska, 18a, 10-651 Olsztyn, Poland. 12.Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland. 13.Department of Pediatrics, Children's Hospital, ul. Niekłańska 4/24, 03-924 Warsaw, Poland. 14.Department of Preventive Health, Poznań University of Medical Science, Smoluchowskiego 11, 60-179 Poznan, Poland. 15.Infectious Diseases Ward, Greater Poland Children's Health Centre; Wrzoska 1, 60-663 Poznań, Poland. 16.Clinical Department of Paediatrics and Nephrology, Voivodeship Complex Hospital L. Rydygiera in Toruń, ul. św. Józefa 53-59, 87-100 Toruń, Poland. 17.Department of Pediatric Oncology, Hematology and Transplantation, Poznań University of Medical Sciences, Szpitalna 27/33, 60-572 Poznan, Poland. 18.Specialist Hospital F. Ceynowy, ul. dr. A. Jagalskiego 10, 84-200 Wejherowo, Poland. 9.Department of Pediatrics and Rheumatology, Specialist Hospital Antoniego Falkiewicza, Warszawska 2, 52-114 Wrocław, Poland. 20.Independent Public Health Care, ul. Sukiennicza 13, 64-500 Szamotuły, Poland. 21.Department of Anaesthesiology and Intensive Therapy, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland. 22.Department of Pediatric Cardiology and General Pediatrics, Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland. 23.Clinical Department of Pediatrics, Mazowiecki Specialist Hospital, ul. Aleksandrowicza 5, Radom, Poland. 24.Children's Hospital “Polanki”, Polanki 119, 80-308 Gdańsk, Poland. 25.Pediatric Ward, Regional Specialist Hospital, ul. Iwaszkiewicza 5, 59-220 Legnica, Poland. 26.Department of Pediatrics, Pediatric Endocrinology and Diabetes, University of Rzeszów, Lwowska 60, 35-301 Rzeszow, Poland. 27.Multidiscyplinary Hospital in Nowa Sól, ul. Chałubińskiego 1, 67-100 Nowa Sól, Poland. 28.Department of Infectious Diseases and Paediatrics, S. Zeromski Hospital in Krakow, Osiedle Na Skarpie 66, 31-913 Kraków, Poland. 29.Chair and Department of Environmental Medicine and Epidemiology, Pediatric Ward, City Hospital in Ruda Śla̧ska, Medical University of Silesia, ul. Wincentego Lipa 2, 41-703 Ruda Slaska, Poland. 30.Congenital Heart Disease and Pediatric Cardiology Department, Silesian Center for Heart Diseases in Zabrze, ul. Marii Curie Skłodowskiej 9, 41-800 Zabrze, Poland. 31.Department of Paediatrics, J. Gromkowski Regional Specialist Hospital in Wrocław, Koszarowa 5, Wrocław, Poland. 32.University Clinical Center: Central Teaching Clinical Hospital, ul. Banacha 1A, 02-097 Warsaw, Poland. 33.Department of Pediatrics, University of Zielona Góra, Zielona Gora, Poland. 34. District Hospital of the name of Doctor T. Chalubinski in Zakopane, ul. Kamieniec 10, Zakopane

Article InfoPublication History

Accepted: July 5, 2022

Received in revised form: July 5, 2022

Received: May 31, 2022

Publication stageIn Press Journal Pre-ProofFootnotes

VSI:COVID-19

Identification

DOI: https://doi.org/10.1016/j.ijid.2022.07.021

Copyright

© 2022 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

User License Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse Permitted For non-commercial purposes: Read, print & download Redistribute or republish the final article Text & data mine Translate the article (private use only, not for distribution) Reuse portions or extracts from the article in other worksNot PermittedSell or re-use for commercial purposes Distribute translations or adaptations of the article
Elsevier's open access license policy ScienceDirectAccess this article on ScienceDirect Related Articles