Kawasaki disease in pediatric isolation ward during COVID-19 pandemic

Background: To our knowledge, a link between an emergence of Kawasaki disease and the ongoing COVID-19 pandemic has not been reported in China. Methods: This study retrospectively analyzed the clinical data of Kawasaki patients admitted to Maternal and Child Health Hospital of Hubei Province from January 1, 2015 to July 31, 2020. Kawasaki patients admitted to the isolation ward from January 1, 2020 to July 31, 2020 as the current cohort and Kawasaki patients admitted to the general wards from January 1, 2015 to December 31, 2019 as the historical cohort were analyzed. Results: The current cohort comprised 15 patients (10 boys and 5 girls, median age 11 months) without severe form. SARS-CoV-2 nucleic acid test was performed in 13 cases and SARS-CoV-2 antibodies (IgM and IgG) was conducted in 11 cases, but no positive results were found. The historical cohort included 89 patients (54 boys and 35 girls, median age 15 months). Comparison between the historical cohort and the current cohort demonstrated that there were no signi�cant differences in age, sex, clinical manifestations, blood routine examination, blood biochemistry, cardiac ultrasound and treatment, but the incidence and the abnormal chest imaging in the current cohort were signi�cantly higher than those in the historical cohort. Conclusion: This study suggested that there may be an association between the emergence of Kawasaki disease with non-severe form and COVID-19 pandemic in Wuhan.


Introduction
In December 2019, an outbreak of pneumonia caused by infection with a new type of coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) occurred in Wuhan, Hubei Province, China.The disease has spread rapidly to other parts of China and many other countries and became a global health emergency [1].The World Health Organization (WHO) named the illness associated with SARS-CoV-2 as the 2019 coronavirus disease (COVID-19) [2].
Because of its characteristics of human-to-human transmission, the National Health Commission of China has published the corresponding guidelines for diagnosis, treatment, prevention, and control of COVID-19 [3,4].According to this guideline, Kawasaki disease with fever as the main manifestation was admitted to the isolation ward during COVID-19 pandemic.In the past few months, alerts on paediatric multisystem in ammatory syndrome temporally linked to SARS-CoV-2 in UK and multisystem in ammatory syndrome in children associated with COVID-19 in USA have been reported [5,6].An observational cohort study in Italy and a multicenter cohort study in France also demonstrated COVID-19 was associated with high incidence of a severe form of Kawasaki disease [7,8].There were also several case reports mentioned that the relationship between Kawasaki disease and COVID-19 [9][10][11].To our knowledge, a link between an emergence of Kawasaki disease and the ongoing COVID-19 pandemic has not been reported in China.In the present study, the clinical characteristics of patients with Kawasaki disease in isolation ward from January 1, 2020 to July 31, 2020 in Maternal and Child Health Hospital of Hubei Province were analyzed retrospectively.The aim of this study was to explore the incidence and features of Kawasaki disease admitted to our isolation ward during COVID-19 pandemic in Wuhan.

Patients involvement
This study retrospectively analyzed the clinical data of Kawasaki patients admitted to Maternal and Child Health Hospital of Hubei Province from January 1, 2015 to July 31, 2020.Kawasaki patients admitted to the isolation ward from January 1, 2020 to July 31, 2020 as the current cohort and Kawasaki patients admitted to the general wards from January 1, 2015 to December 31, 2019 as the historical cohort were analyzed.As a tertiary pediatric referral centre in Wuhan, Hubei Province, China, Maternal and Child Health Hospital of Hubei Province has undertaken the diagnosis and treatment of the majority of febrile children in Wuhan and surrounding area.All the Kawasaki patients were admitted to the isolation ward due to fever during COVID-19 pandemic.Kawasaki disease was diagnosed according to the diagnostic criteria of the American Heart Association [12].This study was approved and patient informed consent was waived by the Medical Ethics Committee of Maternal and Child Health Hospital of Hubei Province.

Data collection
Demographic information (age, sex, and residential location), clinical features (medical history, exposure history, symptoms and sign), imageological examination (chest CT or X-ray, echocardiography), electrocardiograph, laboratory results (white blood cell counts, platelet counts, neutrophils, lymphocytes, Creactive protein, procalcitonin, erythrocyte sedimentation rate, serum ferritin, alanine transaminase, aspartate transaminase, albumin, Mycoplasma pneumoniae, Epstein-Barr virus, in uenza A, in uenza B, adenovirus, SARS-CoV-2 nucleic acid and antibodies), treatment (immunoglobulin, aspirin, corticosteroid, antiviral therapy), length of hospital stay and response to treatment of each patient were obtained from the electronical medical record system of Maternal and Child Health Hospital of Hubei Province.The laboratory data of SARS-CoV-2 nucleic acid and SARS-CoV-2 antibodies for some patients were missing due to the absence of detection reagent.The data was reviewed by three physicians.

Statistical analysis
The counting data are described as percentage(%), non-normally distributed continuous data are presented as medians and interquartile ranges (25-75th).The Mann-Whitney U test or χ2 test were performed for comparison between the current cohort and the historical cohort.Statistical analyses were performed using the SPSS software v.19.0 (IBM Corp.).P<0.05 was considered statistically signi cant.

Results
15 patients with Kawasaki disease were admitted to the isolation ward between January 1, 2020 and July 31, 2020.The incidence was 2.14 per month.There were 10 males and 5 females, and the male-to-female ratio was 2:1.The median age was 11 months (IQR 4 to 17), ranging from 1 month to 4 years and 8 months.The majority (87%) of them were less than 2 years old, and 8 (53%) cases were less than 1 years old.8 (53%) patients were admitted to hospital between January 23 and April 8, which was the period when Wuhan was closed down.All patients were local residents of Wuhan, who lived in Wuhan during COVID-19 pandemic.All patients had no direct exposure history of Huanan Seafood Wholesale Market or wildlife animals (The rst COVID-19 were con rmed to be linked to Huanan Seafood Wholesale Market) [13].All patients had no close contact with the con rmed or suspected COVID-19 patients.Only 2 (13%) patients had a history of eczema, and none of the others had a history of allergy.One patient had favism (glucose-6-phosphate dehydrogenase de ciency).
One patient was preterm and the rest were full-term.
Sodium concentration was decreased in 8 (53%) patients with median 133 mmol/L (IQR 128 to 139).All 15 cases were negative in blood culture.3 (20%) cases were complicated with Mycoplasma pneumoniae infection.1 (7%) patient was associated with Epstein-Barr virus infection.None of the 15 children was infected with adenovirus, in uenza A or in uenza B. SARS-CoV-2 nucleic acid test was performed in 13 cases, but no positive results were found.11 children were tested for SARS-CoV-2 antibodies (IgM and IgG), but there was still no positive result.None of the 15 children met the biological criteria for macrophagic activation syndrome (MAS) according to hemophagocytic lymphohistiocytosis MAS criteria [14], and none developed Kawasaki disease shock syndrome (KDSS) characterized by hypotention or signs of hypoperfusion [15].All 15 patients received 2g/kg intravenous immunoglobulin (IVIG) and 50-80mg/kg aspirin per day.After 3 days of normal temperature, aspirin was reduced to 3-5mg/kg per day for 6-8 weeks or till dilated arteries return to normal.All 15 children received neither corticosteroid or other second-line treatment, nor antiviral therapy.15 patients were sensitive to IVIG because the body temperature decreased to normal on the same day and the in ammation biomarkers decreased gradually.The median of length of hospital stay was 10 days (IQR 10 to 13).So far, 12 patients have been revisited at least once without special complications.Clinical and laboratory features of 15 patients with Kawasaki disease in isolation ward was shown in Table 1.
89 patients diagnosed with Kawasaki disease from January 1, 2015 to December 31, 2019 were analyzed in this study as historical cohort.22 patients lived outside Wuhan and 67 patients were local residents of Wuhan.The total incidence in the past 5 years was 1.48 per month and the incidence of Wuhan local children was 1.12 per month.There were 34731 patients admitted to the general wards from January 1, 2015 to December 31, 2019 and 1462 patients admitted to the isolation ward and the general wards from January 1, 2020 to July 31, 2020.The incidence was signi cantly different between the two cohorts (<0.001).The total number of Kawasaki disease cases in different months in the historical cohort was shown in Figure 2. The higher incidence was found in summer (May, June and July) over the past ve years.Among the 89 patients, 54 boys and 35 girls with the median age 15 months (IQR 7.5 to 30.5). 55 (62%) patients were less than 2 years old, and 34 (38%) patients were less than 1 years old.78 (88%) patients presented with a classic form of the disease, and 11 (12%) patients with an incomplete form.Coronary artery dilatation was observed in 25 (28%) cases.Mitral regurgitation was observed in 12 (13%) patients.
None of the 89 children were complicated with in uenza infection.As shown in Table 2, comparison between the historical cohort and the current cohort suggested that the incidence and the abnormal chest imaging in the current cohort were signi cantly higher than those in the historical cohort (p<0.001 and p=0.003 respectively).There were no signi cant differences in age, sex, clinical manifestations, blood routine examination, blood biochemistry, cardiac ultrasound and treatment between the two cohorts (p>0.05 for all).

Discussion
Kawasaki disease, also called as mucocutaneous lymph node syndrome, was rst reported by a Japanese pediatrician, Dr. Tomisaku Kawasaki in 1967 [16].
Kawasaki disease often occurs in young children, mostly under 5 years of age, with 1.5 times more in boys compared to girls [17].Consistent with this literature report, our study found that the median age of children with Kawasaki disease in the historical cohort was 15 months with the male-to-female ratio 1.54:1.We haven't observed signi cant differences in age and sex between the patients with Kawasaki disease admitted to the isolation ward from January 1, 2020 to July 31, 2020 during COVID-19 pandemic and the historical cohort.An observational cohort study in Italy demonstrated the mean age of children with Kawasaki disease was 7.5 years [7], which is different from our ndings.Epidemiological patterns vary widely from different regions, with incidence varying by race and season.The highest incidence has been reported in Japan with 239/1000000, followed by Korea with 113.1/100000 and Taiwan, China with 69/100000 [18].The incidence of Kawasaki disease hospitalizations has been reported in USA with 19/100,000 in children below 5 years of age [19].In Japan, Kawasaki disease is most prevalent in January (winter) and July (summer), as well as in Korea [20].In USA, the higher incidence in winter and spring has been discovered [21].Our data showed the higher incidence in summer (May, June and July) over the past ve years.But the highest incidence in the current cohort was in March, two months after COVID-19 outbreak in Wuhan.
The pathogenesis of Kawasaki disease is not fully understood, which may be related to infection, immunity and genetic susceptibility [22].Nationwide epidemics of Kawasaki disease have occurred in Japan in the years 1979, 1982, and 1986 [23-25].Seasonal variation have also been observed in many other countries, including but not limited to Europe.These ndings suggested that infection may be a trigger for Kawasaki disease.So far, no speci c pathogen has been con rmed to be absolutely associated with Kawasaki disease.Several case reports have linked Kawasaki disease with many pathogens such as Mycoplasma pneumoniae [26], cytomegalovirus [27], adenovirus, rhinovirus, enterovirus [28], bocavirus [29], parain uenza type 3 and coronavirus OC43/HKU1 [30].Consistent with these reports, Kawasaki disease has been found to be associated with Mycoplasma pneumoniae, enterovirus, Epstein-Barr virus and adenovirus in our historical cohort and Mycoplasma pneumoniae and Epstein-Barr virus in our current cohort.In the past few months several case reports and a time-series analysis have demonstrated that Kawasaki disease is linked to a SARS-CoV-2 infection [31].SARS-CoV-2 nucleic acid test was performed in 13 cases and SARS-CoV-2 antibodies (IgM and IgG) was conducted in 11 cases in our current cohort, but no positive results were found.However, the incidence of Kawasaki disease during COVID-19 pandemic was signi cantly higher than that before COVID-19 pandemic, and Kawasaki disease associated with abnormalities of chest CT were also signi cantly increased.As shown in gure 1, ground-grass opacity (GGO) which is the initial chest CT feature of COVID-19 has not been found in our current cohort, but pleural thickening, brous strips, and subpleural nodules which are the follow-up chest CT changes of COVID-19 have been observed [32,33].SARS-CoV-2 RT-PCR test results of pharyngeal swab specimens are variable and potentially unstable [34], the false-negative rate is as high as 66% on day 21 after infection [35].At present, there are insu cient studies to evaluate the duration of SARS-COV-2 antibodies [36].Considering that Kawasaki disease mainly occurred two months after COVID-19 outbreak in the current cohort, it is possible that these children with CT abnormalities have been previously infected with SARS-COV-2.
The relationship between COVID-19 and Kawasaki disease macrophage activation and Kawasaki disease shock has been reported in Italy and France [6][7][8].In contrast, our data showed no increase in severe form of Kawasaki disease during COVID-19 pandemic in Wuhan.There were no signi cant differences in age, sex, clinical manifestations, blood routine examination, blood biochemistry, cardiac ultrasound and treatment between the historical cohort and the current cohort.The reason for this inconsistency may be related to race and genetic difference.We also compared our data with those of Europe, and we found the median age of children with Kawasaki disease in Wuhan were signi cantly younger than that reported in Europe [6-8].We presumed that the immune response in younger children was not as strong as in older children, so there was no severe form of Kawasaki disease or multisystem in ammatory syndrome reported in Wuhan.
The present study has some limitations.This is not a multicenter retrospective analysis and may not perfectly represent the overall incidence of Kawasaki disease during COVID-19 pandemic in Wuhan.Further clinical studies with lager cohorts in China are required to con rm the ndings of this study.
In conclusion, the present study retrospectively analyzed the characteristics of Kawasaki disease in isolation ward from January 1, 2020 to July 31, 2020 in a tertiary pediatric referral centre in Wuhan, China.This study found that Kawasaki disease mainly occurred in young children (87% were less than 2 years old) in Wuhan, and there were no MAS and KDSS during COVID-19 pandemic.All children with Kawasaki disease responded well to IVIG and aspirin.Although no de nitive evidence of SARS-CoV-2 infection in these children with Kawasaki disease has been found, but the incidence of Kawasaki disease during COVID-19 pandemic was signi cantly higher than that before COVID-19 pandemic, and Kawasaki disease associated with abnormalities of chest CT were also signi cantly increased.This study suggested that there may be an association between the emergence of Kawasaki disease with non-severe form and COVID-19 pandemic in Wuhan.The typical chest CT ndings in the historical cohort (red arrow).A, Bilateral pleural thickening.B, Subpleural nodules.C, Fibrous strips.

Declarations
The total number of Kawasaki disease cases in different months in the historical cohort.
The total number of Kawasaki disease cases in different months in the historical cohort.

Table 1 .
Clinical and laboratory features of 15 patients with Kawasaki disease in isolation ward

Table 2 .
Comparison between the current cohort and the historical cohort