MIS-C is a novel disease associated with the infection of SARS-CoV-2 in children. It is characterized by the severe systemic inflammation and may lead to the damage and dysfunction of multiple organs, particularly the cardiac and coronary artery system. Children seem to develop symptoms and signs of MIS-C in the post-infection phase of COVID-19 instead of the acute infection phase and may progress into an advanced stage quickly [12••]. It is important to identify MIS-C and to initiate immunomodulatory therapies in a timely manner so as to help correct the hyperinflammatory state and prevent or minimize any target organ injuries. In this systematic review, we comprehensively reviewed reported MIS-C cases from published and preprint studies of various designs to provide an updated evidence on epidemiology, clinical spectrum, laboratory and imaging findings, management, and short-term outcomes. Our work will be able to give health care professionals and the general public a detailed picture about this newly emerged disease in this pandemic. Furthermore, we provide a unique comparison of reported MIS-C cases in HICs to LMICs to identify any regional differences regarding the clinical course of MIS-C.
Risk Factors for MIS-C
Previous studies report certain groups to be at a higher risk of contracting the SARS-CoV-2 or developing a severe form of the infection. It has been reported that African Americans (different age groups, especially children) are at a higher risk of developing COVID-19 compared to other ethnicities [9, 24,25,26]. Other risk factors that have been reported to be associated with SARS-CoV-2 infection include the following: Hispanic ethnicity [25, 26], male gender , and living in a high-density community [26, 27]. Regarding the risk factors for developing MIS-C in the pediatric COVID-19 patients, current evidence is limited. We found in this systematic review that comorbidities in general are associated with a higher risk of MIS-C, while being African Black and obese/overweight reported a lower risk.
Our analysis revealed that children with at least one comorbidity have a higher risk of developing MIS-C once infected with SARS-CoV-2, particularly those with neuromuscular or respiratory diseases. However, in a prospective observational cohort study of 124 children  (63 confirmed or probable MIS-C cases and 61 cases with MIS-C-like presentations but with an alternative diagnosis), researchers found that only 35% of MIS-C cohort had underlying conditions. On the other hand, MIS-C cases included in our study have a mean age of 8.1 years with a slightly male predominance, which is consistent with the previous systematic reviews on MIS-C . Nonetheless, neither age or sex could predict the occurrence of MIS-C once infected with SARS-CoV-2. Over 27% cases of the included MIS-C cases are African Black and Hispanic White each, followed by non-Hispanic White (21.27%). Although these groups take up a large proportion of MIS-C cases, which is consistent with previous studies [29,30,31,32,33,34], a comparable risk of developing MIS-C was observed. Instead, being African Black was associated with a lower risk for MIS-C presentation. This may be due to the disproportionately greater COVID-19 disease burden in these ethnic and racial groups [9, 24,25,26], which is resulting from complex factors, including nutrient deficiency, overcrowding living condition, and inadequate access to health care [26, 27].
Excessive production of inflammatory cytokines, as a direct reaction to the virus or as a postinfectious phenomenon, is associated with disease severity in adults with COVID-19 . In adults, male sex, older age, obesity, diabetes, and certain pre-existing medical conditions have been identified as biological vulnerabilities for more severe COVID-19 outcomes [36,37,38]. In children and adolescents, age younger than 1 year of age, obesity, and pre-existing comorbidities including chronic cardiac and respiratory diseases are widely reported to be associated with more severe clinical outcomes [39, 40, 41••, 42]. Some studies also identified the presence of diarrhea  and significantly elevated CRP  as predictors of severe disease in children with COVID-19. Studies on factors predicting more severe outcomes in MIS-C patients are limited. Abrams et al.  identified that age older than 5 years was strongly associated with more severe outcomes in MIS-C. We identified only two studies comparing the risk of ICU admission due to MIS-C in various ethnic groups, four on comorbidities, and six on gender. In the pooled analysis, females, African American children, and those with any comorbidity are more likely to have a more severe clinical course and be admitted to ICU after developing MIS-C.
Clinical Spectrum and Common Laboratory Findings
MIS-C was reported to have a very wide spectrum of presenting signs and symptoms, ranging from persistent fever and some characteristic features of Kawasaki disease to the most severe shock and multiorgan failures [12••]. Another systematic review conducted by Ahmed et al. found out that the most common symptoms of MIS-C are fever, gastrointestinal symptoms (abdominal pain, vomiting, and diarrhea), rash, and conjunctivitis . Of 662 children, 60.1% included required vasopressor support and/or fluid resuscitation due to shock as a result of systemic inflammation and impaired cardiac output . Previously published systematic reviews of MIS-C report higher prevalence of gastrointestinal symptoms in the majority of cases, rashes of varying descriptions in less than 50% of cases, and respiratory tract symptoms in a small proportion of cases [29,30,31,32,33,34, 45]. In this systematic review, we concluded the most prevalent symptoms of MIS-C include fever, gastrointestinal symptoms (especially abdominal pain, vomiting, and diarrhea), rash, and conjunctivitis. More than one-third of the cases included in our systematic review experienced shock (37.19%, 95% CI 35.40–38.98%) as a result of systemic inflammation and impaired cardiac output, and 63.91% of MIS-C cases were admitted into ICU.
While the most common clinical symptoms of COVID-19 in the pediatric population include fever, cough, nausea or vomiting, and diarrhea , there is overlap and distinctive features between MIS-C and pediatric COVID-19 regarding their clinical symptoms [29, 31].
The laboratory findings of MIS-C from our synthesis include significantly elevated inflammatory markers: CRP (92.59%), ferritin (60.53%), ESR (55.30%), and procalcitonin (39.05%). Over 50% MIS-C patients observed elevated cardiac markers consistent with previous reviews [29,30,31,32,33,34, 46, 47].
MIS-C and Kawasaki Disease
MIS-C shares some similarities with KD, including male predominance, cases always presenting with persistent fever, shock, signs and symptoms of a systemic inflammatory response and multiorgan injuries, and their good response to steroids [12••]. Most notably, they can both lead to coronary artery aneurysm [12••, 48,49,50,51,52]. But there are differences between MIS-C and KD. MIS-C seems to impact an elder children population, more prevalent in African Black and Hispanic White instead of in the Asian group, and associated with greater elevation of inflammatory markers [14••, 17, 19, 22]. Our findings in this systematic review are consistent with previous literature. In the pooled analysis, children of African Black origin are more prevalent in MIS-C, different from KD, which is Asian-dominant. MIS-C cases are less commonly presented with some of the typical KD characteristic symptoms, such as rash, conjunctivitis, and cervical lymphadenopathy, and are more likely to present with pericardial, pleural effusion and mitral regurgitation in ECHO. Despite the overlapping symptoms of MIS-C and KD, less than one-fifth of MIS-C cases fulfill the diagnosis criteria of incomplete or complete KD (18.54%, 95% CI 16.94–20.14%, and 14.54%, 95% CI 13.10–15.97%, respectively).
Current Treatment Plan and Outcomes for MIS-C
Some of the commonly employed treatment regimens for MIS-C include IVIG, steroid, antibiotics, anticoagulation, and inotropes. A national consensus from the UK [53••] suggests IVIG at a dose of 2 g/kg as the first-line therapy for children with PIMS-TS, which can be repeated to those not responding or partially responding to the first dose and intravenous methylprednisolone (10–30 mg/kg) as the second-line therapy. For patients who do not respond to the first- and second-line therapies, biological therapy can be commenced based on a multidisciplinary discussion and decision. They also recommended that intravenous antibiotics should be commenced in all patients, and antiviral therapy with remdesivir as the first choice might be considered for patients with positive SARS-CoV-2 RT-PCR or antigen testing result. Low-dose aspirin should be given and continued for a minimum of 6 weeks. We found in this systematic review that the management plan for MIS-C varies in different studies but was generally similar in HICs and LMICs.
If identified and managed timely and appropriately, MIS-C patients generally have a favorable outcome. Our review revealed that the majority of MIS-C cases (95.21%) fully recovered while only 2.41% died from this syndrome, consistent with other former systematic reviews [32,33,34, 45, 54]. There is paucity of reports on the long-term follow-up of MIS-C, possibly due to the fact that it is a newly emerged disease. A recent report [55••] on 45 children (< 21 years old) from New York, USA, who were followed at 1 to 4 weeks, 1 to 4 months, and 4 to 9 months post-discharge, was published. The median time of follow-up was around 6 months. The follow-up showed encouraging medium-term outcomes with 76% requiring intensive care but no mortalities, including rapid return to baseline of inflammatory markers and significant cardiac abnormalities in the majority of cases with immune derangements including lymphocytosis may extend up to several months after initial hospitalization. Continued caution and case reporting with follow-up are recommended to ensure timely management of children with MIS-C and to further inform pediatricians.
Comparisons Between HICs and LMICs
In this systematic review, we further disaggregated our included patients according to the World Bank income levels and compared the epidemiology, clinical spectrum, treatment, and outcomes between the LMIC and HIC. Although with generally similar presentations and treatment plans, MIS-C cases in LMICs had a lower percentage of ICU admission and mechanical ventilation application but a higher risk of death. It may be explained by the relatively high disease burden and limited health care resources in LMICs.
Strengths and Limitations
Our review was conducted in a systematic manner and comprehensively included and analyzed current available data on MIS-C. It provided an overview of the epidemiology, clinical spectrum, management, and short-term outcomes of this newly emerged disease so as to shed some light on current diagnosis, management, and future researches of MIS-C. But our review also has some limitations. Firstly, although the quality of the majority of included studies was shown to be fair or good, a lot of included studies were case reports/series, limiting its methodological quality. Secondly, original studies investigating the risk factors for developing MIS-C and leading to a more severe clinical course of MIS-C are limited. Furthermore, many children with COVID-19 are asymptomatic and COVID-19 cases of certain demographic and socioeconomic groups may be underreported. It also makes it difficult to identify and confirm the risk factors for developing MIS-C. Thirdly, case definition in different studies may vary, particularly at the early stage of the pandemic. Together with various study design, it resulted in the great heterogeneity of our included studies.
Future Research Directions
The pathogenesis and risk factors of MIS-C are still unclear. And it remains challenging to make an early identification and a precise diagnosis for MIS-C in the clinical setting due to its wide clinical spectrum and great overlap with other infectious disease and autoimmune disorders in clinical presentations. Researches focusing on these areas are crucial in guiding either public health policy making or clinical diagnosis and management of MIS-C.
As a newly emerged disease, we have very limited evidence on the long-term outcome of MIS-C. Particularly, cardiac abnormalities were not only restricted to critically ill children 28, making it necessary to follow up all patients with MIS-C with and without immediately apparent cardiac complications for long-term cardiac outcomes.
Furthermore, greater efforts should be made to improve the health equity of MIS-C patients in LMICs or from certain vulnerable population groups. For example, most of the immunomodulator medications advised to treat MIS-C are either unavailable or unaffordable in LMICs. Although the immunosuppressive steroids are affordable and accessible, their safeness, appropriate type, dose, route, and duration of use should be carefully studied in the LMICs context given the high prevalence and limited diagnostic capacity to exclude tuberculosis and HIV infections there .