In December 2019, the first case of a new coronavirus infection with the severe acute respiratory syndrome (SARS-CoV-2) was registered in China for the first time. Since then, the COronaVIrus Disease 2019 (COVID-19) pandemic has rapidly developed into a global health emergency around the world.

This disease is observed relatively less often in children than in adults (1–5% of diagnosed diseases among the population at the beginning of the pandemic) (1). At the moment, it is up to 16% of all COVID-19 cases (2). The clinical course of COVID-19 in children, as in adults, mainly manifests with fever and respiratory symptoms; however, more frequently it proceeds in an asymptomatic or mild form, without development of severe pneumonia (3, 4). At the same time, since April 2020, there have been many reports that a new coronavirus infection may be associated with a childhood hyperinflammatory condition that fully or partially meets the criteria of Kawasaki disease (KD) (5).

KD is an acute systemic vasculitis of unknown etiology, affecting predominantly children under 5 years, characterized by fever, bilateral conjunctival hyperemia, oropharyngeal mucosa changes, erythematous rash, erythema and indurative palms and feet edema, and cervical lymphadenopathy. Approximately 20–25% of untreated patients develop changes in coronary arteries of varying severity from asymptomatic dilatation to giant aneurysms, thrombosis, myocardial infarction, and sudden death (6).

For the first time, the suspicion of the possible connection between COVID-19 and KD was put forward by Jones et al., who reported a case of classic KD in a 6-month-old girl with a positive PCR result for SARS-CoV-2 (7). Also among the first who described this problem were groups of researchers from Italy (8) and France (9). However, this disorder occurs in older children than KD. It is also often manifested with gastrointestinal symptoms (diarrhea, abdominal pain, vomiting) and heart damage (myocarditis, pericarditis), often leading to myocardial damage and shock, while these clinical manifestations are less common in KD (10). The severity and pronounced similarity of the symptoms of this new syndrome and KD caused terminological dilemmas—in addition to the name Kawasaki-like syndrome, others appeared—hyperinflammatory shock, Kawa-COVID, a multisystem inflammatory syndrome in children (MIS-C), or pediatric inflammatory, multisystem syndrome temporarily associated with SARS-CoV-2 (PIMS-TS), and since July–August 2020, two of the latter names have mainly been fixed in the literature. MIS-C is quite rare, and the incidence at the beginning of the pandemic in children was about 2 per 100,000 people or <1% of children with confirmed SARS-CoV-2 infection (11). However, in a more recent study, the frequency of MIS-C cases is 1:4,000 children who have suffered COVID-19 infection (12). Despite the similarities in the clinical picture, the diseases might have different outcomes and treatment approaches. Thus, KD required IVIG 2 g/kg as the first treatment line, followed by repeated IVIG, corticosteroids, and TNF-a inhibitors. MIS-C required systemic corticosteroids, IVIG, IL-1, and IL-6 inhibitors. Interestingly, anti-IL1 and IL-6 treatment did not show its efficacy in KD as anti-TNFa (13).

Our study is aimed to compare clinical and laboratory features of MIS-C and KD and to create the discrimination criteria between two diseases.

We are presenting the experience in diagnostics of MIS-C associated with COVID-19 at several pediatric clinics in Russia (St. Petersburg, Irkutsk) comparing them with a historical cohort of patients with KD. In general, the data obtained about both diseases are comparable with previously published studies. Special attention is focused on this new pathology due to the rapid development and high frequency of life-threatening complications—shock and multiorgan failure, as well as heart damage and coagulopathy (9, 11, 20). There are two sets of criteria for MIS-C diagnostics: the WHO criteria and CDC-criteria. We used WHO criteria, which might be to some extent focused on cardiac involvement, as CDC-criteria are more relevant to hyperinflammation, but all of our patients satisfied both sets of criteria (14, 21). Fortunately, MIS-C is a rare condition, which involves one of each 4,000 children, infected with COVID-19 (12). The obtained data demonstrate similarities and differences between MIS-C and KD. Both of these conditions are considered as hyperinflammatory syndrome with multisystem involvement, on an immunopathological basis under the influence of a trigger factor which is a new coronavirus infection for MIS-C; for KD, a specific trigger has not been found yet.

In general, there is much in common between these two diseases, including many similarities in clinical phenotypes, and some patients with MIS-C fulfill the AHA criteria for KD (5). In both diseases, fever, mucocutaneous manifestations, conjunctivitis, hand and foot erythema/edema, and cervical lymphadenopathy are observed, but we noted that rash in MIS-C was more diffuse and extensive compared to KD (8, 9, 20, 22). In our research, these symptoms were also quite similar in both studied conditions. Patients with MIS-C were admitted to the hospital earlier than KD patients were, possibly due to raising concerns for the families the coronavirus presents. The main unifying sign of both diseases, except fever, mucocutaneous and lymph-node involvement, and systemic inflammation biomarkers, is the involvement of the heart and coronary arteries (9, 20, 22). Cardiac involvement in KD manifested with development of CA aneurisms, their subsequent thrombosis, and heart attack (5, 23). MIS-C is predominantly characterized by the acute myocardial injury with increased troponin I level and reversible dilatation of CA with rear CA thrombosis and heart attack (9, 11, 20, 22).

The main discriminative factors between two diseases are onset age, high CRP, thrombocytopenia, increased D-dimer, and GI involvement. MIS-C occurs in all age groups, but still the majority of patients are high school students, those with KD usually are younger, and 76% of them are children under 5 years old (24). The median onset age of the affected children of MIS-C in our study is 8.9 (5.3, 11.8) years, which is comparable to the previously published results where the median age ranges from 6 to 12 years (11, 22, 25, 26). However, it is important to emphasize that MIS-C can also occur in children under 1 year of age (27). Also, a hyperinflammatory condition similar to MIS-C in young adults after COVID-19 has been reported (28).

Diversity between the two illnesses is also obvious as there are signs and symptoms with high frequency in MIS-C which are less commonly or rarely presented in KD patients. For example, gastrointestinal symptoms are more common for MIS-C according to many studies including our observation (11, 22, 29). It should also be noted that among the studied patients with gastrointestinal disorders in our MIS-C group, one had acute appendicitis, which required laparoscopic appendectomy, and the “white” appendix was removed. Similar cases are also described in previously published works (30, 31). In addition, among significant differences between MIS-C and KD there are myocardial injury, hypotension/shock, and neurological disorders in MIS-C patients that are less frequent in KD (8, 20, 22, 32). Sixty-five percent of MIS-C patients admitted to ICU had CNS involvement and had serous meningitis and cerebral venous thrombosis as the most serious complications. Unless cardiac involvement can be presented in both diseases, there are some differences in the nature of cardiac findings. Thus, myocarditis is more common in MIS-C patients, while CA aneurisms are more typical for KD (9, 32–34).

Speaking of laboratory values, elevated inflammatory biomarkers were seen in both conditions in our study as well as in previously published articles (8, 20, 29). However, for example, CRP levels were significantly higher in MIS-C patients in our study, as well as in previously published articles (29). For assessment of cytokine storm syndrome, we applied HScore, which was created earlier for hemophagocytic lymphohistiocytosis. HScore >105 was associated with the severest signs of MIS-C: myocarditis [OR = 4.2 (95% CI: 1.5, 11.5), p = 0.005], pericarditis [OR = 7.1 (95% CI: 2.4, 21.6), p = 0.0003], shock [OR = 3.7 (95% CI: 1.4, 10.3), p = 0.009], and GI involvement [OR=5.4 (95% CI: 1.3, 22.3), p = 0.013]. HScore is a simple tool which might be used for assessment of severity of MIS-C. Additionally, there is a difference in platelet levels in MIS-C and KD patients in our study, with median of 185 and 520^*10⁹/l, respectively. Thrombocytosis is typical for KD, but less common in MIS-C patients, who quite often have a tendency toward thrombocytopenia, especially at onset or during the peak of the disease (8, 20, 22, 29). Additionally, elevated biochemical markers of cardiac injury and highly elevated ferritin and D-dimer are typical for MIS-C patients (20, 22, 29). These findings seem to be less common for KD patients. For example, in our study median ferritin was 366 μg/l in the MIS-C group and 120 in the KD cohort, and D-dimer levels were also significantly different in studied conditions, 1,855 and 584 ng/ml, respectively. However, it is also reported that elevated D-dimer can actually be the risk factor of CA damage in KD patients (35).

MIS-C is close in manifestations to Kawasaki-shock syndrome as they are united by the fulminant development of heart injury, similar gastrointestinal symptoms, hyponatremia, and hypoalbuminemia (34). Factors causing the development of shock in KD are not fully understood, but an important role in its pathogenesis is played by more pronounced inflammation and especially intense and very rapidly developing vasculitis with thrombosis and endothelial damage (36). Probably, endothelial damage in MIS-C differs from KD, due to the unique characteristics of the pathogen SARS-CoV-2 and its affinity to the endothelium. The vascular wall damage due to COVID is primarily caused by the virus penetration into the cells of the vascular endothelium through the ACE2 receptor, and then after a certain period of time immuno-mediated endothelial damage develops (37).

The pathogenetic basis for both MIS-C and KD is the dysregulation of the innate immune response, and as a result in both diseases there is an excessive production of pro-inflammatory cytokines, up to a cytokine storm, which occurs much more frequently in MIS-C than in KD. Gruber et al. (38) detected the presence of autoantibodies in patients with MIS-C against not only endothelial but also gastrointestinal and immunocompetent cells, and obviously this is due to a number of pathophysiological and clinical differences. Neutralizing antibodies against SARS-CoV-2 can activate IL-18 and IL-16, myeloid chemotaxis, and activation of lymphocytes, monocytes, and natural killers, which lead to neutrophil activation, hypercoagulation, and thrombosis (38). These changes are not typical for children suffering from acute COVID-19, but characteristic for severe forms of COVID-19 in adults (39). NETosis on the basis of MIS-C in children and severe forms of COVID-19 in adults may provoke severe cytokine storm and inflammation leading to microthrombosis and irreversible involvement of the cardiorespiratory system (40). The main unresolved question is if MIS-C is a unique self-limited condition, related to COVID-19 infection, or it is the severest variant of KD triggered by the SARS-CoV-2 virus. The viral etiology of KD was previously described, and different types of coronaviruses (HCoV-NL63 and HCoV-NL229E) were mentioned as a possible cause of KD, but other studies did not confirm it (41–44).

The DScore can be used to differentiate the diagnostic of having MIS-C from KD, accompanied with other diagnostic tests and procedures. Further investigations are required.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

MK, LB, VC, VS, and YK contributed to the conception and design of the study. IA, ED, AM, EI, TK, OE, VM, LS, and OK organized the database. MK and IA performed the statistical analysis. MK, LB, and IA wrote the first draft of the manuscript, wrote sections of the manuscript, and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. MK, LB, IA, ED, AM, OE, EI, TK, VM, LS, VS, YK, OK, and VC have contributed equally to all of the following aspects: conception, acquisition of data, drafting, and revising the article. All authors contributed to the article revision, read, and approved the submitted version.

This work was supported by the Russian Foundation for Basic Research (Grant No. 18-515-57001).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.