COVID- 19 pandemic has spread throughout the world at an alarming rate . Initial reports suggested that children who got infected are highly resilient to the disease and generally progress with a mild course [1, 11]. Awareness has increased regarding MIS-C among the paediatricians and health care professionals after second wave as compared to first wave. Literature suggests MIS-C affects only 0.6% of patients < 21 years of age infected with SARS Cov-2 [12, 13] and there are certain limitations in its recognition and diagnosis . Another major concern was that despite an asymptomatic or milder course of COVID disease children could still develop MIS-C . The literature reports that MIS-C typically manifests 3–4 weeks after SARS-CoV-2 infection . This may explain why many children had positive antibodies to SARS- CoV-2, but negative RT-PCR at the time of MIS-C evaluation . In our study RT-PCR is also positive in 17% of cases.
As described by Riphagen et al., hyperinflammatory shock is a common element in MIS-C  These findings were substantiated in the systematic review by Ahmed M et al, which included 662 children (17). Now the testing guidelines for COVID-19 RT-PCR and other inflammatory markers have now been streamlined in most parts of India. As there is clinically significant overlap with other common diagnoses, there is high probability that clinicians are either missing the milder cases  or even over-diagnosing similar presentations of KD or toxic shock syndrome as MIS-C. Whitaker, et al. have proposed three clinical patterns of MIS-C presentation viz, those with shock and cardiac involvement, those with fever and elevated inflammatory markers without features of KD, and those who had classical features of KD (18). An overlap of several children can occur having mucocutaneous features of KD, raised inflammatory markers, and those who present with shock.
The inflammatory storm observed in MIS-C is much more intense than KD and TSS, though they few common features. Some differentiating clinical characteristics found in MIS-C includes age of presentation, GI disturbances like vomiting, diarrhoea, and abdominal pain. One more important difference to identify between KD and MIS-C is that approximately 5% of children with Kawasaki’s disease presented with cardiovascular collapse , where as 60.2% of children with MIS-C presented with shock (17).
The reason why few children are more susceptible to develop MIS-C is still unknown. In the systematic review it was observed that the African American/ Afro-Caribbean population had more proportion of MIS-C. MIS-C can even present as an acute surgical abdomen. The abdominal pain in MIS-C can be so severe that some were presumed to have appendicitis or surgical abdomen. In studies by Belhadjer et al. and Dasgupta, children received urgent abdominal surgery, but ultimately found the patients had mesenteric lymphadenitis [20, 21]. As per the definition of MIS-C, neutrophilia and lymphocytopenia were frequent. The average neutrophils percentage was 80.7%, a finding that was reported in 99 children from New York by Dufort et al (average = 82.3%) . We had similar kind of Neutrophilia in our study. Out lymphocyte percentage also aligned with that of study by Dufort et al. As expected, inflammatory markers were universally elevated, additionally elevated serum ferritin, Troponin and liver enzymes were significant laboratory parameters observed in patients with shock. Another study from India by Jain S et al, had similar findings (22). Dufort, et al.  reported KD/ KD like illness in 36%, myocarditis in 53%, shock in 10% and coronary aneurysms in 9% of their cohort of children with MIS-C from New York. In a study from Chennai, India, Dhanalakshmi, et al. reported hypotension requiring vasoactive medications in 57% of patients presenting with PIMS-TS, and coronary artery changes in 16% .
In classifying patients with MIS-C with KD like illness, clinicians need to differentiate this from classical KD in patients from COVID-19 endemic areas . There is significant epidemiological evidence that MIS-C is distinct from KD. When compared with those of classical KD children with MIS-C are older and sicker. Feldstein, et al.  have observed 50% MIS-C patients presenting with cardiovascular shock leading to vasopressor or inotropic support as compared to only 5% of children with KD in the United States. Similarly, in our series, the mean age of patients was 6.7 years, which is older than the age of presentation for KD. The percentage The cardiac biomarkers (NT pro BNP, Troponin and CPK-MB) are of course indicative of myocarditis and can be used to predict clinical deterioration and shock.
Cardiac manifestations are frequently found in children with MIS-C. Some children developed poor ejection fraction or dilated coronaries in the later part of illness inspite of normal echocardiogram during admission. The most common echo finding was decreased ejection fraction (45%) in systematic review. In line with these findings, a recent study revealed that adults who recently recovered from COVID-19 had ongoing cardiac involvement and myocardial inflammation . Accordingly, children undergoing evaluation for MIS-C should have a baseline 2D Echo, ECG, and repeat imaging to follow cardiac function and artery changes. Close follow-up will be important as the long-term implications of MIS-C cardiac involvement are currently unknown. Elevated troponin levels in individuals with COVID-19 are independent prognostic markers of poor outcome . This implies that all patients with MIS-C would need serial echocardiographic surveillance for coronary and myocardial involvement in the acute and convalescent phase of illness, even if the initial echocardiogram was normal.
Our findings in first wave are comparable to those published in systematic review in which 61% of children required vasopressor support and/or fluid resuscitation, (17). In our series, following first wave 45% required inotropic support, but in the cumulative data, 28% required inotropic support. In the US MIS-C series, IVIG (77%) and systemic glucocorticoids (49%) were used in most patients . In the UK series, 71% received IVIG and 64% corticosteroids. Three patients received anakinra and eight received infliximab. Inotropic support was required in 47% 18]. In our series, 69% of the patients received low dose methyl prednisolone and 12% pulse dose; and 19% IVIG. Biologicals such as tocilizumab/infliximab were not used. The relatively lower usage of IVIG is due to high cost of this treatment, which unfortunately is often a deciding factor for treatment decisions in our population.
Based on our small numbers, we do not believe that at present, levels of acute phase reactants can reliably predict the subsequent clinical course of the child. Generally, the short-term outcomes of MIS-C have been promising. The Mortality was 1.8% in systematic review . In another large study involving 570 children, the mortality was 1.8% (28). In our series one child expired (0.96%), who has pre-existing cerebral palsy. Although significant proportion of children were critically ill and had multisystem inflammation, all responded to prompt administration of anti-inflammatory agents, i.e. steroids and IVIG.
The children who presented after first wave had higher incidence of respiratory distress at admission, myocardial dysfunction, shock at admission and blood product requirement. The possible mechanisms need to be further investigated. However, the differences could be attributed to late referrals from peripheral hospitals in first wave because of lack of awareness at that time and also due to lack of access for transport because of strictly imposed lockdown. After first wave national wide treatment protocols and guidelines were established, which helped many paediatricians to initiate the treatment early. However, we didn’t see recurrence in any child in the second wave.
These results are analysis of ongoing hospital based prospective study. We were rigid in our case selection to include only those patients who themselves or whose immediate family contacts had confirmed SARS-CoV-2 antigen or seropositivity. Hence, we may have missed mild cases. Our data is expected to add to the limited data on this condition from India, and assist clinicians in identifying and managing MIS-C. Frequent hemodynamic assessment with repeated functional Echo and optimal use of inodilators like milirinone can improve the outcomes among those with myocardial dysfunction.