Kawasaki Disease Outbreak in Children During COVID-19 Pandemic.

Background In response to the recent information about the outbreak of Kawasaki disease (KD) in children connected to SARS-Cov-2 pandemic, we would like to present a group of six patients hospitalized from March to May 2020 with an inammatory disease similar to KD. Findings There were four girls and two boys, aged from 15 months to 16 years. They all presented with fever lasting at least ve days, irritability, bilateral nonexudative conjunctivitis, lymphadenopathy, mucus membrane changes, rash, edema. Neither the patients nor the other members of the patients' households had a positive history of COVID-19 infection. None of the six children had a positive PCR result for SARS-CoV-2 or a positive results for antibodies to SARS-CoV-2. All patients received empiric antibiotic therapy. Four patients were diagnosed with KD. Three children received standard treatment. One boy did not respond and received an additional 14-days course of methylprednisolone. In two girls, the diagnosis of KD was not made. All patients survived Conclusion Finding a correlation with the Covid-19 pandemic is dicult regarding the situation in our country. According to ECDC, in May 2020 Poland wass still before the peak of the epidemy. The intention of this article is to report that increased hospitalization of children with the inammatory syndrome is also observed in countries with low levels of transmission of the SARS-Cov-2 virus. Our observation may broaden the knowledge of new inammatory syndrome, which is not necessarily caused by SARS-Cov-2 but may be worsened by co-infection.


Introduction
The etiology of Kawasaki Disease (KD) remains unclear. For many years infectious background was suspected. Many viruses (e.g. seasonal coronavirus -HcoV NL63, Epstein-Barr virus), bacteria, fungi were suspected -but nothing was proved (1). There is no doubt that genetic factors are important, but they cannot explain seasonal variations and temporal clustering of KD cases. In temperate regions, the peak of the incidence of KD occurs in the winter season. So far, there were several large epidemics of KD in Japan and in the United States (2). It has been hypothesized that tropospheric wind patterns arising from China are associated with KD peaks (3). It suggests that KD could be induced by an airborne pathogen from this area (3). Countries with large outbreaks of SARS-CoV-2 (France, Italy, Spain, UK, US) have seen the occurrence of cases of paediatric in ammatory, multisystem syndrome (PIMS) in the late stages of the rst wave of the COVID-19 pandemic (4,5,6,7,8,9). Lucio Verdoni and colleagues in the article" An outbreak of severe Kawasaki-like disease at the Italian epicenter of the SARS-CoV-2 epidemic: an observational cohort study" published in Lancet described a recent outbreak of KD in Italy (5). Clinicians in Europe and the United States have identi ed clusters of similar cases (3,4,5,6,7,8,9). Observed epidemy in KD disease in may countries is attributed to the Sars-Cov-2 pandemic.

Material And Methods
Between march 1st and May 31st 2020, at the Infectious Diseases Department in St. Joseph`s Children's Hospital in Poznan (Poland), six children were hospitalized with an in ammatory disease similar to KD. We analysed only patients with fever without identi ed source and no response to antibiotic therapy. On admission, laboratory tests including complete blood count, C-reactive protein (CRP), potassium, sodium, and transaminase levels, urinalysis, blood and urine cultures, chest X-ray and abdominal ultrasound were performed. Children underwent cardiology consultation.
KD was diagnosed in patients with fever lasting 5 days or longer accompanied by four or more of the clinical criteria : bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy (1).
A child is presenting with persistent fever, in ammation (neutrophilia, elevated CRP, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurological disorder) with other additional clinical, laboratory or imagining and electrocardiogram (ECG) features.
Children ful lling full or partial criteria for Kawasaki disease may be included.
Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus.
SARS-CoV-2 PCR testing positive or negative Results There were four girls and two boys, aged from 15 months to 16 years. They all presented with fever lasting at least seven days -not responding to antibiotic treatment, irritability, bilateral nonexudative conjunctivitis, cervical lymphadenopathy, mucus membrane changes: dry, cracked lips, pharyngitis, strawberry tongue, rash, peripheral edema. In ammatory markers were elevated: neutrophilia with lymphopenia, signi cantly increased C-reactive protein, ferritin levels, and hypoalbuminemia. In some patients, raised troponin levels and transaminitis were also observed. Echo and ECG were performed in all patients -in one coronary artery dilatation was found.
Two patients were diagnosed with pneumonia. Abdominal ultrasound revealed lymphadenopathy, ascites, hepatosplenomegaly.
Details are presented in the table 1.
There was no COVID-19 history, or COVID-19-compatible symptoms could be either elicited in the history of the child or a household member. None of the three tested children were positive for SARS-CoV-2 by PCR. All patients underwent serology tests: none was positive for IgG or IgA antibodies.
Coinfection with other pathogens has been investigated, and no pathogens have been detected: blood cultures were negative, there were no serological markers of Ebstein-Barr virus infection (EBV), PCR testing for respiratory syncytial virus (RSV), and in uenza was negative.
All patients received empiric antibiotic therapy. All children ful lled PIMS-TS case de nition criteria proposed by the Royal College of Paediatrics and Child Health. Four patients were diagnosed with Kawasaki Disease. Three children received standard treatment according to the American Heart Association: intravenous immunoglobulin (IVIG) 2 g/kg given over 12 h and aspirin 50 mg/kg. One boy did not respond to IVIG and received an additional 14-days course of methylprednisolone (11).
In two girls, the diagnosis was not made. The rst patient was a 6-years old girl; she was admitted on the seventh day of fever. While hospital staying, she remained afebrile, and over ten days, other symptoms gradually resolved; cardiac echo was normal after two and six weeks from the beginning of a fever. The oldest girl had markedly increased in ammatory markers (CRP, ferritin), high NT-Pro-BNP (N-terminal pro-B-type natriuretic peptide), radiographic signs of pneumonia, but no changes were detected on echo. Fever subsided, and her condition improved without IVIG.
All patients survived, and their health status improved gradually with time.

Discussion
About 230 suspected cases of the in ammatory multisystem syndrome associated with SARS-CoV-2 infection (PIMS-TS) have been reported in EU/EEA countries and the UK in 2020 (4). The described increase in KD is similar to the situation observed in other countries (5,6,7,8,9). In past years we had a few patients with KD. In 2019 we had seven patients and in 2018 six (all cases in autumn/winter season). Finding a correlation with the Covid-19 pandemic is di cult regarding the situation in our country. Poland is a country with low transmission of SARS-CoV-2. As of 31st May we had over 20 000 cases (53cases /100,000); in our region (Wielkopolska), we had around 2000 cases (58.8cases/100,000)-mostly localized in provinces in the southern part of Wielkopolska. In those provinces, Covid-19 cases were mainly detected in long-term healthcare facilities for the elderly.
Since March 13, people were advised to self-isolate, schools, and kindergartens are closed. As pediatricians, we observe markedly decrease in infections in children. The number of children consulted in an emergency room and hospitalized is much lower comparing to previous months. In other countries, PIMS is reported relatively late during the waning tail of the rst epidemic curve -so this is not the moment for Poland. According to ECDC, in May 2020 Poland was still before the peak of the epidemy .
One possible mechanism that causes PIMS in children could be via antibody-dependent enhancement (ADE) (4,7). All the examined patients were serologically negative when tested for the presence of IgA or IgG antibodies against SARS-CoV-2. The negative results can't be explained by the low quality of test. Both molecular and serological tests were performed in nationaly certi ed laboratories. Negative tests results can be explained by the clinical context. Patients had no proven contacts with people with Covid-19, family members were healthy. So in the described patients, the in ammatory condition was not related to SARS-CoV-2 infection.
The intention of this article is to give information that an increase in hospitalization of children with an in ammatory syndrome is also observed in countries with low transmission of the SARS-CoV-2 virus. Our observation can broaden the knowledge on a new in ammatory syndrome, which is not necessarily caused by SARS-CoV-2, but it can be worsened by coinfection. This is an analysis of medical data, no personal data were analyzed, so there was no need for ethics committee approval.

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Competing interests
All the authors declare no con ict of interests.

No founding
Authors' contributions EG substantial contributions to conception and design, and acquisition of data, and analysis and interpretation of data; participate in drafting the article, revising it critically for important intellectual content; and give nal approval of the version to be submitted JW had substantial contributions to conception,; participate in drafting the article, revising it critically for important intellectual content; and give nal approval of the version to be submitted.
MF had substantial contributions to analysis and interpretatioubmitted.n of data; participate in drafting the article, revising it critically for important intellectual content; and give nal approval of the version to be submitted.
DJ-L had substantial contributions to conception, design and interpretation of data; participate in drafting the article, revising it critically for important intellectual content; and give nal approval of the version to be submitted.