There is a growing concern over emerging cases of MIS-C worldwide. MIS-C shows features similar to KD or KDSS in addition to multiple organ inflammation with elevated inflammatory markers in the blood. Although clusters of cases of MIS-C from Europe and North America have been reported during the COVID-19 pandemic, no case has been reported from East Asia. Given the high prevalence of KD or KDSS in East Asia, no report of MIS-C during the pandemic is unusual and merits further investigation. This difference in epidemiology may indicate why MIS-C is different from KD or KDSS, despite having similar features.
The novel multisystem inflammatory syndrome was first suggested by Verdoni L et al. (8) in Italy, and clusters of more cases have since been reported in Europe and the United States. Accordingly, WHO/Centers for Disease Control and Prevention issued a definition of MIS-C and urged awareness and alertness of the disease (6) (9). Our case fulfils all the suggested case definitions.
It was difficult to diagnose our patient’s illness and identify its causes, who was hospitalized for severe enteritis with negative PCR results for SARS-CoV-2. During admission, further symptoms consistent with MIS-C had appeared, and the patient condition improved in response to IVIG. Enteritis symptoms, such as abdominal pain or diarrhea, are rare in KD. However, enteritis symptoms appeared to be common in MIS-C. In a case series from the United Kingdom (UK), diarrhea or abdominal pain were noted on all patients with MIS-C (10).
In our patient, PCR and IgM antibody results for SARS-CoV-2 were negative, but the IgG result was positive, which may represent a prior COVID-19 infection. In a case series from the UK, the PCR results were positive in only 50% children with MIS-C; the remaining 50% children with negative PCR results showed IgG antibodies against SARS-CoV-2 (10). Another report of MIS-C cases in New York demonstrated that 8 of 17 patients tested positive for SARS-CoV-2 on PCR, while the other 9 patients tested positive on serology (11). PCR yields negative results after 3–4 weeks of a SARS-CoV-2 infection. Serum IgM disappears within 6–7 weeks of infection, while IgG persists for several months (12). In previous studies, the interval between the onsets of COVID-19 and MIC-S symptoms were reported as 6 weeks for 24% patients with MIS-C (median: 21 days) (7) (13). Thus, although our patient had no obvious history of exposure to any COVID-19 patient, he may have been exposed to the virus at the airport or somewhere else on his way back to Korea from the Philippines. Although our patient had no respiratory symptoms of COVID-19, IgG antibodies against SARS-CoV-2 were highly positive, and lung parenchymal consolidation was detected on CT. An asymptomatic prior infection could be a cause of MIS-C in our patient.
It is unclear whether MIS-C is caused by a direct SARS-CoV-2 infection or delayed immune response after the infection. It has been suggested that antibody-dependent enhancement of hyperinflammation leads to a more severe outcome in dengue fever (14). Further, in SARS-CoV infection, anti-spike IgG reduced wound healing and provoked lung injury by skewing lung macrophage response and proinflammatory cytokines (15). Likewise, SARS-CoV-2 may induce the hyperinflammatory condition in multiple organs with the antibody-dependent mechanism.
Our patient showed overlapping features of incomplete KD and/or KDSS. However, the features differed from those of KD or KDSS in the following respects: 1) older age; 2) normal cardiac enzyme levels and function and minimal valve regurgitation; 3) coronary dilation in the acute stage and prompt normalization within 3 days after a single IVIG treatment (16) (17). In a recent multicentre study comparing MIS-C with KD, KDSS, and TSS, patients with MIS-C were older and higher levels of inflammatory markers than those with KD, KDSS, or TSS (14).
There is no gold standard serological test for anti-SARS-CoV-2 antibodies. We used various anti-SARS-CoV-2 antibody test kits with different target antigens and methodologies to minimise the possibility of false-positive and/or non-specific reactions; all the tests yielded concordantly positive results. In addition, we evaluated IVIG products administered to the patient at serial dilutions and found that all tests using IVIG showed negative IgG results. For our patient, multiple serological tests suggested a diagnosis of COVID-19.
To our knowledge, no case of MIS-C has been reported in East Asia. Thus far, cases have been concentrated in Europe and North America; however, clinicians from other countries should be aware of this novel syndrome in cases of incomplete KD or KDSS, even when there is no clear history of contact or symptoms of COVID-19, and consider immunomodulatory therapy. Further research and international cooperation are required to investigate the immunopathogenesis of COVID-19 in children.