Pediatric Inflammatory Multisystem Syndrome (PIMS) Did Occur in Poland during Months with Low COVID-19 Prevalence, Preliminary Results of a Nationwide Register

Pediatric inflammatory multisystem syndrome (PIMS) is a new entity in children, likely associated with previous coronavirus disease 19 (COVID-19) infection. Most of the reports about PIMS come from countries particularly hit by the COVID-19 pandemic. Our aim was to investigate the nature of inflammatory syndromes in Poland (country with low COVID-19 prevalence) and to perceive the emergence of PIMS in our country. On 25 May 2020, we launched a nationwide survey of inflammatory syndromes in children for retrospective (since 4 March 2020) and prospective data collection. Up to 28 July, 39 reported children met the inclusion criteria. We stratified them according to age (<5 and ≥ 5 years old) and COVID-19 status. The majority of children had clinical and laboratory features of Kawasaki disease, probably non-associated with COVID-19. However, children ≥5 years of age had PIMS characteristics, and nine children had COVID-19 confirmation. This is, to our knowledge, the first report of the PIMS register from a country with a low COVID-19 prevalence, and it proves that PIMS may emerge in any area involved in the COVID-19 pandemic. In a context of limited COVID-19 testing availability, other risk factors of PIMS, e.g., older age, should be considered in the differential diagnosis of inflammatory syndromes in children.


Introduction
Since late April 2020, a growing set of articles has been published describing Pediatric Inflammatory Multisystem Syndrome (PIMS) -a new inflammatory entity in children, temporally and geographically associated with the coronavirus disease 2019 (COVID-19) pandemic [1][2][3][4][5][6][7][8][9]. The first definition of PIMS had been announced by the Royal College of Paediatrics and Child Health (RCPCH) on 1 st May [10]. Multisystem Inflammatory Syndrome in Children (MIS-C) is an alternative name proposed in the United States of America (USA) [11] and adopted by the World Health Organization (WHO) [12]. Unlike PIMS, MIS-C definition requires confirmed SARS-CoV-2 infection or COVID-19 exposure. Approximately 1000 cases of PIMS and MIS-C have been reported as of July 2020, with the vast majority of reports from countries particularly hit by COVID-19 pandemic. Epidemiological studies revealed that an abrupt increase in PIMS incidence occurs about 4-5 weeks after the peak of local COVID-19 cases [5,7].
If a connection with COVID-19 is real, unusual clusters of severely ill children observed in the United Kingdom (UK), France, or the USA, may not occur in countries where COVID-19 is not as prevalent. Moreover, there are concerns that remarkably severe clinical course of PIMS emerging from reports published so far, with 50-80% of children requiring intensive care unit (ICU) admission, may represent an extreme point of the broader spectrum of the post-infectious inflammatory response to COVID-19 [3,13]. Thus, in countries with lower COVID-19 prevalence, we may expect PIMS to be more scattered in distribution and more diverse in the clinical picture, which needs to be investigated.
Poland (population over 37.5 M citizens, highly homogeneous society with predominant Caucasian race) had a relatively low COVID-19 prevalence. As of 28 th June, nearly 44,000 confirmed COVID-19 cases had been registered [14]. The incidence rate in Poland was approx. 1,000/1 M, almost 3-fold less than in France, over 4-fold less than in the UK or Italy and 12-fold less than in the USA [15] (Error! Reference source not found.) The lower infectious rate might partially result from a lower testing rate (Poland, 52,101 / 1 M citizens). Thus, the discrepancy in testing didn't correspond to the incidence rate (testing rate was similar in France, only 2-fold higher in Italy, 3-fold higher in the USA and 4-fold higher in the UK). In Poland, children accounted for 0.8-2.8% of all laboratory-confirmed cases, similar to other countries [16]. Our aims were: to investigate the nature of inflammatory syndromes in Poland during the COVID-19 epidemic and perceive the emergence of PIMS in our country. On 25 May, we launched nationwide surveillance of pediatric inflammatory syndromes: the MOIS-CoR Study (MultiOrgan Inflammatory Syndromes COVID Related). In this report, we present clinical and laboratory characteristics of the first 39 children with inflammatory conditions, including confirmed PIMS, diagnosed over a period from 4 th March (when the first case of COVID-19 in Poland was diagnosed), to 28 th July 2020.

Experimental Section
The voluntary surveillance for retrospective (since 4 th March) and prospective data collection was initiated under the National Consultant of Pediatrics auspices. Anonymized patient data from 34 pediatric hospitals from all over the country (Error! Reference source not found.) were extracted from electronic and paper records and collected through online form developed for that purpose. Before the surveillance was launched, reporting clinicians underwent an online training, which included the current state of knowledge about PIMS and unified diagnostic approach to such patients recommended by the study's expert committee. Patient management was at the discretion of the relevant treating clinicians.  5. SARS-CoV-2 polymerase chain reaction (PCR) or serology result could have been positive or negative. Due to limited availability and reliability of serologic testing, proven or likely COVID-19 criterion was not a condition determining inclusion to the registry.
KD and aKD were defined following the American Heart Association (AHA) guidelines [17]. TSS was established based on modified criteria by the Centers for Disease Control and Prevention (CDC) [18,19]. MAS was diagnosed based on the Paediatric Rheumatology International Trials Organization (PRINTO) criteria for MAS classification in systemic juvenile idiopathic arthritis [20]. The definition of the inflammatory syndrome was based on the WHO MIS-C definition with the exclusion of SARS-CoV-2 confirmation [12]. Detailed inclusion criteria and case definitions are presented in Table 1. Fever for at least 5 days and 4 from the following symptoms: a) Erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa b) Bilateral bulbar conjunctival injection without exudate c) Rash: maculopapular, diffuse erythroderma, or erythema multiforme-like d) Erythema and edema of the hands and feet in acute phase and/or periungual desquamation in subacute phase e) Cervical lymphadenopathy (≥1.5 cm diameter)

Incomplete (atypical) Kawasaki disease (aKD) case definition:
Fever for at least 5 days and 2 or 3 from the above symptoms OR infant with unexplained fever for at least 7 days AND CRP ≥ 3 mg/dl and/or ESR ≥ 40 mm/hr AND 1) at least 3 of the following: a) Anemia for age b) PLT ≥ 450 000 ×10 9 /L after the 7 th day of fever c) Albumin ≤ 3 g/dL d) Elevated ALT e) WBC count of ≥15 000×10 9 /L f) Urine ≥ 10 WBC/hpf OR 2) Changes in echocardiogram suggesting KD
For patients who met the inclusion criteria, we collected demographic data, past medical history, data on COVID-19 exposure, clinical symptoms, physical examination findings, laboratory, imaging, and cardiologic tests results, treatment, and outcome. Three independent, experienced researchers verified the fulfilment of inclusion criteria and the diagnoses.
Most of the findings were interpreted as descriptive and exploratory. Results are presented as counts and percentages for categorical data and medians and interquartile ranges (IQRs) for continuous data, according to COVID-19 evidence and age groups (below or at least five years of age). Groups were compared with Mann-Whitney, and ANOVA Kruskal-Wallis tests were appropriate. Data statistical analyses were done with the use of Excel 2016 and Statistica 12 (Stat Soft). Results with p-value <0.05 were considered statistically significant.

Discussion
Our study is the first to our knowledge report of pediatric inflammatory diseases surveillance, from the country of low COVID-19 prevalence. The number of laboratory-confirmed cases of PIMS in our cohort proves that PIMS may emerge in any pandemic area.
The vast majority of children registered in our survey fulfilled KD or aKD diagnostic criteria. Their clinical characteristics and laboratory results were typical for this well-known inflammatory disease of childhood [3,17]. A substantial proportion of children in our cohort probably had KD nonassociated with SARS-CoV-2 infection.
Because of unknown SARS-CoV-2 status in nearly half of the patients, we performed stratification by age (Table 2- 4). We found that children over five years of age presented with several distinct features consistent with PIMS from previous reports [3,5,6]. Older children had more frequently gastrointestinal symptoms (79% vs. 52%), with a predominance of abdominal pain, nausea, and vomiting. Musculoskeletal symptoms were also more prevalent in the older age group. Lymphadenopathy was observed more commonly in younger children. Children over five years of age had significantly lower lymphocyte count (mean value in the range of lymphopenia) and much higher ferritin values than younger group. We found the distribution of symptoms in separate age groups to be similar to described for PIMS by Dufort et al. and Feldstein et al. [5,6].
The features characteristic of PIMS were even more definite when comparing COVID-19 positive versus negative patients (Table 4). Clinical presentation of the nine patients who had confirmed SARS-CoV-2 infection or exposure history was consistent with findings described in current reports [3,5,6,21,22]. These patients were older, with more common gastrointestinal involvement and headaches. Furthermore, compared to SARS-CoV-2 negative patients -they developed lower lymphocyte count, platelet count, and hyponatremia, higher CRP, and ferritin level (all of them statistically significant) tended higher BNP and troponin concentrations (not statistically significant).
The exact incidence and risk of developing PIMS are challenging to assess. The estimated incidence of confirmed PIMS in Poland as of July is approximately 0.1 per 100,000 children and adolescents, which is 20 times lower than that reported in the New York State by Dufort et al. [5]. The small number of COVID-19-related PIMS cases in Poland is another argument supporting that PIMS is a post-infectious complication of COVID-19 in children. Simultaneously, children in our cohort had a milder clinical course than those registered in other countries. One of the possible explanations is specific homogeneous racial and genetic background. However, given the small number of cases, this should be interpreted with caution. On the other hand, the clinical presentation of children with confirmed PIMS in our group supports the broader range of PIMS manifestations. Higher vigilance of PIMS among clinicians involved in our register at the early stage of the pandemic may explain a higher number of benign cases.

Limitations
The lack of historical data about the incidence and clinical characteristics of pediatric inflammatory diseases in Poland makes it impossible to compare our findings to pre-pandemic data. A relatively small group of patients in our register necessitates further surveillance to obtain more data and perform reliable statistical analyses. The number of health centers involved in the study is limited, but new units are still recruiting.

Conclusions
PIMS may emerge in any country involved in the COVID-19 pandemic. Distribution of PIMS may be more scattered and clinical presentation milder in a context of low background COVID-19 prevalence. Rising awareness of this new pediatric condition among clinicians is essential for prompt diagnosis and appropriate approach to such patients. In context of limited SARS-CoV-2 testing availability other risk factors of PIMS, e.g. older age, should be considered in differential diagnosis of inflammatory syndromes in children.