Discussion

KD presents more commonly in children with Asian ancestry, and surprisingly, MIS-C is rare in Asians, the latter more is commonly reported in children of African ancestry and Hispanic.^{Reference Whittaker, Bamford and Kenny1,Reference Gardner-Medwin, Dolezalova, Cummins and Southwood2} In the seminal paper of KDSS by Kaneyage et al. in San Diego, Hispanic patients were overrepresented with no Asians.^{Reference Kanegaye, Wilder and Molkara3} Before the COVID-19 pandemic, KDSS was considered to be a distinct and unique form of KD.^{Reference Gamez-Gonzalez, Moribe-Quintero and Cisneros-Castolo4} KDSS is defined as an episode during acute KD of hypotension and shock requiring volume expanders, infusion of vasoactive agents, or transfer to the ICU. KDSS differs from haemodynamically stable KD in terms of older age, frequent gastrointestinal manifestations, neurological manifestations, severe cardiac dysfunction, pericarditis, hypoalbuminemia, hyponatremia, and thrombocytopenia, with higher levels of CRP and troponin, all features are encountered in MIS-C.^{Reference Noval Rivas, Porritt, Cheng, Bahar and Arditi5} In PP-KDSS, gastrointestinal manifestations were present in 74.6% of the patients. Patients with MIS-C often present with an acute abdomen mimicking appendicitis.^{Reference Whittaker, Bamford and Kenny1} Coronary artery dilation or aneurysms have been described in 6–24% of patients with MIS-C. Echocardiographic include valve regurgitation, pericardial effusion, and marked LV dysfunction, again paralleling the course of PP-KDSS.^{Reference Whittaker, Bamford and Kenny1} Hypercoagulability with abnormalities in the coagulation cascade has been noted with elevated levels of D-dimers and fibrinogen. Notwithstanding, these laboratory findings are non-specific and are altered in PP-KDSS. Whittaker et al. compared MIS-C patients with PP-KDSS patients and found the former tended to be older, present with higher white blood cell count, CRP, and more lymphopenia, while alanine aminotransferase and D-dimer levels were similar.^{Reference Whittaker, Bamford and Kenny1} Remarkably, patients with MIS-C often present with thrombocytosis in the convalescent phase. Recently, superantigen activity of SARS-CoV2 have been implicated in the pathogenesis of MIS-C, similar to toxic shock syndrome.^{Reference Noval Rivas, Porritt, Cheng, Bahar and Arditi5} In PP-KDSS, TSS-1 was the most frequent diagnosis at the time of admission.^{Reference Gardner-Medwin, Dolezalova, Cummins and Southwood2} Superantigens have long been implicated in KD pathophysiology. In PP-KDSS, superantigens were implicated contrasting to hemodynamically normal-KD, and have been thought to have a role in this presentation of KD.^{Reference Iglesias-Amaya, Quezada-Ortega and Godinez-Victoria6} SARS-CoV2 has been shown to infect endothelial cells leading to endotheliitis.^{Reference Calcaterra, Mehta, Fanos and Bassareo7,Reference Varga, Flammer and Steiger8} MIS-C share more features with PP-KDSS than with TSS-1, particularly with TSS-1 lacking coronary arteries abnormalities (Table 1). Treatment of MIS-C is analogous to KDSS with IVIG, steroids, and biologics.^{Reference Whittaker, Bamford and Kenny1} Recently, the presence of SARS-CoV2 in the gastrointestinal tract with a breakdown of intestinal permeability and subsequent trafficking of the virus antigens into the bloodstream has been found.^{Reference Yonker, Gilboa and Ogata9} Importantly, treatment with larazotide, a tight junction regulator that improves intestinal permeability, was associated with clinical response in MIS-C.^{Reference Yonker, Gilboa and Ogata9} The clinical similarities and response to similar therapy support the notion that MIS-C is part of the KD spectrum, and with all these arguments, authorities in the field have concluded that MIS-C may be a new presentation of KD triggered by a single virus.^{Reference Sancho-Shimizu, Brodin and Cobat10} The parallelism of MIS-C with PP-KDSS reflects the racial predisposition, possible similar pathophysiology (superantigens in both), and infectious aetiology of KD located in the GI tract. These cases open research questions such as the genetic susceptibility of MIS-C (as an inborn error of immunity or superantigen and HLA-related) and the presence of an infectious gastrointestinal trigger, the role of superantigens, and the possible efficacy of larazotide in non-SARS-CoV2-KDSS.

Table 1. Demographic and clinical characteristics of patients with MIS-C and KDSS.

KDSS = Kawasaki disease shock syndrome, data are from references 2 and 3; MIS-C = Multisystemic inflammatory syndrome in children.