Coronavirus disease 2019 (COVID‐19): A systematic review of 133 Children that presented with Kawasaki‐like multisystem inflammatory syndrome

Abstract Kawasaki‐like disease (KLD) and multisystem inflammatory syndrome in children (MIS‐C) are considered as challenges for pediatric patients under the age of 18 infected with coronavirus disease 2019 (COVID‐19). A systematic search was performed on July 2, 2020, and updated on December 1, 2020, to identify studies on KLD/MIS‐C associated with COVID‐19. The databases of Scopus, PubMed, Web of Science, Embase, and Scholar were searched. The hospitalized children with a presentation of Kawasaki disease (KD), KLD, MIS‐C, or inflammatory shock syndromes were included. A total number of 133 children in 45 studies were reviewed. A total of 74 (55.6%) cases had been admitted to pediatric intensive care units (PICUs). Also, 49 (36.8%) patients had required respiratory support, of whom 31 (23.3%) cases had required mechanical ventilation/intubation, 18 (13.5%) cases had required other oxygen therapies. In total, 79 (59.4%) cases had been discharged from hospitals, 3 (2.2%) had been readmitted, 9 (6.7%) had been hospitalized at the time of the study, and 9 (6.7%) patients had expired due to the severe heart failure, shock, brain infarction. Similar outcomes had not been reported in other patients. Approximately two‐thirds of the children with KLD associated with COVID‐19 had been admitted to PICUs, around one‐fourth of them had required mechanical ventilation/intubation, and even some of them had been required readmissions. Therefore, physicians are strongly recommended to monitor children that present with the characteristics of KD during the pandemic as they can be the dominant manifestations in children with COVID‐19.


| INTRODUCTION
Since December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the family Coronaviridae causing coronavirus disease 2019 (COVID-19) emerged in Wuhan, China, and then became a global health challenge. This was the third epidemic of the large family Coronaviridae, which induced SARS and the Middle East respiratory syndrome at the beginning of the present century. 1,2 The authors' knowledge of COVID-19 was thus based on two previous experiments in their early phases, that hyperinflammation caused by macrophage-activating syndrome and cytokine storm release (CSR) was involved in the pathogenesis of COVID-19. [3][4][5][6] Initially, COVID-19 patients were identified with symptoms such as dry cough, fever, dyspnea, headache, weakness, and lethargy, which later appeared with gastrointestinal (GI), neurological, and cutaneous manifestations. 7,8 Early on, it seemed that children were not the target groups and they were less likely to be affected, so there were a small number of reports on childhood illnesses. 9,10 After a while, the surge of comparable reports of children attending In this respect, MIS-C refers to a hyperinflammatory systemic condition that shares numerous similar features of KD such as lymphadenopathy, diarrhea, elevated inflammatory biomarkers, prolonged fever, skin rash alongside some separate specifications like older onset, the predominance of abdominal symptoms, cases with left ventricular systolic dysfunction and acute heart failure (AHF). 11,15 The present study was designed and implemented to demonstrate the relationship between severely ill cases with KD/ MIS-C and COVID-19.

| Search databases and search strategies
This study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines 16 on July 2, 2020, and updated on December 1, 2020, to identify the studies on KD/MIS-C associated with COVID-19. To this end, the relevant studies were searched using the databases of Scopus, PubMed (i.e., MEDLINE), Web of Science, Embase (Elsevier), and Scholar. The following search keywords were also used: "coronavirus," "COVID-19," "coronavirus and infection," "SARS-CoV-19," "2019 novel and coronavirus," "Kawasaki," "hyperinflammatory," "inflammatory syndrome," "Kawasaki-like," and "MIS-C." The keywords list utilized in the search is provided as a Supporting Information appendix. The PRISMA flow diagram of the study selection process is also illustrated in Figure 1.

| Eligibility criteria
The pediatric patients (0-≤18 years of age) with more than 1 day of subjective or measured fever (≥100.4°F/38°C) and hospital stay, that presented with at least KD, Kawasaki-like disease (KLD), MIS-C, or inflammatory shock syndromes, with the evidence of COVID-19, and with confirmed SARS-CoV-2 infection using nasopharyngeal RT-PCR or antibody (viz. serological) testing were included in this study.
Moreover, irrelevant studies, conference abstracts, and duplicates were excluded.

| Data extraction and quality assessment
Two independent and blinded reviewers extracted the data and then performed crosschecking. A third reviewer also resolved the disagreements via consensus. Accordingly, the data were extracted: Regarding the quality assessment, two independent reviewers evaluated the risk of bias of the included cohort studies using the modified version of the Newcastle-Ottawa Scale, 19 and the National Institutes of Health Quality Assessment tool for case series/reports 20 (Tables S1 and S2). With regard to the symptoms of patients, skin rash (n = 74, 55.6%) was the most common one followed by conjunctivitis (n = 65, 48.8%), and then lip and oral cavity changes in 43 (32.3%) patients, as summarized in Table 2. Other KD clinical features such as GI symptoms (n = 97, 72.9%), hypotension (less than 90/50, n = 45, 33.8%), and pulmonary abnormalities (n = 35, 26.3%) were also present in these patients ( cases had been discharged from hospitals, 3 (2.2%) had been readmitted, 9 (6.7%) had been hospitalized at the time of the study, and 9 (6.7%) patients had expired. Likewise, the outcomes had not been reported in the rest of the patients (n = 33).

| RESULTS
In the initial analysis, the measured pooled mean (SE) for inflammatory cytokines such as C-reactive protein (CRP), erythrocyte F I G U R E 3 Cardiac MRI for four children with a clinical diagnosis of acute myocarditis in the setting of COVID-19-related Kawasaki-like symptoms. The top panel demonstrates minimal pericardial effusion on cine images. The second panel demonstrates increased T2-STIR signal intensity with average ratios between myocardium and muscle more than 2 in patient 2 (12-year-old male), patient 3 (11-year-old female), and patient 4 (6-year-old female). The third panel demonstrates abnormal native-T1 mapping, which was more than 1100 ms in patients 2, 3, and 4 and normal in patient 1 (8-year-old female). The bottom panel demonstrates absence of late gadolinium enhancement (LGE) in patients 2 and 3. Myocardial null times were recognized as too short in patient 4 but could not be repeated due to lack of further patient cooperation; however, a review of Look-Locker images and additional sequences revealed no LGE. Images obtained from Blondiaux et al. 18

| Patients with a death outcome
In this systematic review, a total of 9 (6.7%) patients, mostly male dominance (66.6%) expired due to a wide variety of reasons. Severe heart failure and cardiac arrest played a predominant role in the mortality of these patients (n = 6). As patients Nos.

| DISCUSSION
As with the COVID-19 pandemic and its progress, the incidence of patients admitted with KD and other related diseases and symptoms such as KLD and MIS-C has increased, so there have been several reports from different countries. 21,22 In this study, available evidence published updated globally until December 1st were systematically reviewed, and hyperinflammatory condition in children following COVID-19, threatening their lives, were reported. We found that more than half of children with KLD associated with COVID-19 had been admitted to PICUs, a quarter had required mechanical ventilation/intubation and even some of them had been required readmissions. Moreover, a 6.7% mortality rate was observed in children with KLD associated with COVID-19 that mostly due to severe heart failure, cardiac arrest, and refractory hypotension. Additionally, the male gender could be recognized as a poor prognostic factor with a fatality rate of two times higher than the female.
Despite more than half a century since the initial reports of KD, no clear cause has been thus far identified, and no specific pathology has been recognized. 23 Considering the higher number of cases with KD after the outbreak of viral respiratory diseases, the most accepted hypothesis is the strange response of the immune system to With an overview of the gender distribution of the patients developing KD in association with COVID-19, male dominance had been apparent, which had the same order with KD alone. 30 Among the death reports in the reviewed cases, the ratio of male to female had been 2:1, so that the male gender could be recognized as a poor prognostic factor, which was consistent with mortality in adults with COVID-19, with the fatality rate of male two to three times higher than female. In adults, this effect had been hypothesized to be dependent on males with higher angiotensin-converting enzyme 2 expression, X chromosome immunological consequences, and hormonal differences 31,32 ; So, ignoring the latter, the two other causes could be generalized to children.
The study results revealed that GI manifestations were also prevalent in patients exhibiting KD associated with COVID-19, with a higher incidence rate than those in both non-COVID-19 KD and children with Also, this study revealed a higher mortality rate among patients with KD associated with COVID-19, compared to each of them alone, given that nine children had died and one had proceeded to brain death. 35,36 Hyperinflammation state and augmented cytokine production in KD amidst the CSR associated with COVID-19, leading to several increased cytokines was further presumed causative in the progress of this condition that could make it more common in COVID-19; however, its inflammatory profile was different from that of COVID-19. The increased CRP and ferritin observed in the reviewed cases were supportive here.
Nevertheless, the role of high troponin levels and hypotension in patients should not be missed, which could show serious cardiovascular diseases and their effects on higher mortality rates, insofar as inotropes had particular importance in the treatment of these patients following intravenous immunoglobulin and antibiotics ( Table 3). scarcity of cases in other parts of the world. The vast majority of demised patients in this review had circulation problems, and they suffered from heart failure and refractory hypotension despite aggressive therapy that didn′t respond to efforts. In most of them, the cytokine profile is different from whatever is generally seen in COVID-19 patients. Echocardiography of these patients mostly has various degrees of cardiac dysfunction, and in some cases, the arterial aneurysm was observed. It seems that their condition gets more critical when the cytokine storm begins to rise; while, in most of the above patients (death patients), the number of cytokines at the time of death is much higher than from the first examination. An equivocal point that needs further investigation is cytokine profile correlation with prognosis in these patients. However, we encounter a CSS in most patients who die; not all patients with high levels of inflammatory cytokines had complicated conditions. Although differences in the approach and treatment of patients can be one of the causes of this problem, due to the similarity of drug treatment and their focus on suppressing the immune system, other factors, including genetic variations, might be remarkable in this regard. One of the expired patients (No. 87) had a history of G6PD deficiency. The G6PD deficiency was introduced as a predisposing factor in the increasing incidence of COVID-19 because it plays a pivotal role in coronavirus viral gene expression and viral particle production. So, the action of this deficiency in the increase of mortality rate should also be investigated. 37 Among the limitations of this review study, at first, incomplete datasets for numerous properties, which made it impossible to present appropriate comparisons and conclusions. Second, the duration of followups was inadequate, leading to the omission of their long-term sequel.
Thirdly, selection bias in the studies concerned in some countries was undeniable, as they might have been written in different languages rather than English. Considering the studies were slightly heterogeneous and their information was not comparable in some characteristics, multidisciplinary research in this field is recommended to shed light on the obscure dimensions of this condition.

| CONCLUSION
This systematic review established that approximately two-thirds of children with KLD associated with COVID-19 had been admitted to PICUs. Moreover, around one-fourth of them had required mechanical ventilation/intubation and even some of them had required readmissions.
Therefore, pediatricians and physicians are strongly recommended to monitor children that present with fever, GI symptoms, and other characteristics of KD during the pandemic as they can be the dominant manifestations in children with COVID-19. Accordingly, irreversible complications can be prevented through early diagnosis and treatment.