Although SARS-CoV-2 has not been definitively proven as the cause of MIS-C, the fact that MIS-C appeared during outbreaks of COVID-19 in Europe and the USA is highly suggestive. If the condition becomes less common as the pandemic terminates, it will further support the relationship [8].
The CDC case definition of MIS-C is extremely broad and would be met in many infectious and inflammatory conditions of childhood including acute COVID-19, KD, viral infections, systemic onset juvenile idiopathic arthritis, toxic shock syndrome, and HLH. The course of MIS-C is generally favorable if timely and proper management is provided. Such hyperinflammatory syndrome is different in presentation and management than the classic COVID-19 disease with severe respiratory involvement [8].
Fever is the cardinal symptom in patients with MIS-C, with 100% of patients developing a fever, whereas a third of the classic SARS-CoV-2 patients without MIS-C do not present a fever. This syndrome is characterized by gastrointestinal symptoms, cutaneous and may be neurologic manifestations with elevation of inflammatory markers, but the most serious are hypotension, shock, and acute cardiac dysfunction. There were a high proportion of MIS-C patients requiring vasoactive drugs even with conserved cardiac function which may indicate an important element of vasoplegia in these patients [6].
It should be remembered that acute COVID-19 can also affect multiple organ systems including increased coagulation tendency [9].
Although elevation of inflammatory markers is detected in patients with COVID-19, patients with MIS-C exhibit lower levels of lymphocytes and LDH, higher levels of CRP and PCT, neutrophils, and a higher lymphocyte/neutrophil ratio in addition to the higher level of cardiac troponin.
In adults, hyper-inflammation is more frequent in the context of COVID-19 bilateral pneumonia, while in children it is more frequent in patients with mild or absent respiratory symptoms presenting gastrointestinal symptoms and shock fulfilling MIS-C criteria, whereas patients with classic SARS-CoV-2 typically show respiratory symptoms [6].
The overlap between the two conditions—COVID-19 and MIS-C—was described as differing manifestations of the new clinical syndrome in a latent class analysis study published by the CDC as initial findings of 570 children in the USA. The study divided patients of MIS-C into three class groups based on the shared characteristics with KD and acute COVID-19; in their described class 2, the clinical and laboratory manifestations of MIS-C overlapped with those in acute COVID-19. These patients had the most respiratory symptoms and highest prevalence of nasopharyngeal RT-PCR positivity for SARS-CoV-2, and likely had acute COVID-19 [10]. This was similar to the presentation of our patients while many other studies reported that MIS-C can develop weeks after COVID-19 infection, suggesting its immune-mediated cause [3, 11, 12].
In our two reported cases, there were combined manifestations of severe pulmonary COVID-19 evidenced by the respiratory symptoms along with the extensive pulmonary affection in the CT (CO-RADS 4 and 5) (described in Figs. 1 and 2), and manifestations of severe MIS-C evidenced by the critical presentation of shock in the first case and picture of infection in the second one in addition to compromising cardiac functions evidenced by echocardiography and elevated cardiac enzymes level. Moreover, all the criteria of MIS-C according to CDC case definitio n[4] were fulfilled; fever, multi-system affection, increased markers of inflammation, evidence of COVID-19 (positive serology for SARSE-CoV-2) with no other obvious microbial cause of inflammation (where all cultures were negative). This overlap might result from the development of MIS-C soon after symptomatic acute COVID-19 illness.
In our two patients, the manifestations of both conditions, COVID-19 and MIS-C came simultaneously, but both had negative RT-PCR from nasopharyngeal swab while tested COVID-19 positive by serology in contradictory to class 2 described by CDC where nasopharyngeal swab PCR reported positive [6]. CO-RADS 5 in patient’s CT was a supporting evidence for diagnosis of COVID-19 in spite of the negative PCR. The majority of published cases of MIS-C have had positive serologic testing for SARS-CoV-2 and less commonly positive RT-PCR testing from nasopharyngeal testing, suggesting that this syndrome may be post-infectious and associated with lower viral burden when compared with acute early infection. Other opinions suggests that MIS-C may be caused by an underlying deregulation of the immune system, with the viral infection triggering a hyperinflammatory response rather than being a direct expression of SARS-CoV-2 infection [1, 13].
So, we have two unique cases different from the classic severe pulmonary COVID-19, classic MIS-C, and even different from the CDC described class of overlap between them.
The outcome of both patients was generally favorable; they were discharged from hospital within 10 days with follow-up at the COVID-19 outpatient clinic.