**3. Presentation of COVID-19 in children**

The presentation of COVID-19 in children differs somewhat from the presentation seen in adults. COVID-19 in children most commonly present with fever and cough [15] and gastrointestinal symptoms such as diarrhea and vomiting. Gastrointestinal symptoms are reported in a considerable portion of cases [1, 3, 15] which is less characteristic of adult cases. While some patients develop respiratory distress syndrome, the severe form of COVID-19 is less common in children as compared to adults [15] and the mortality rate of COVID-19 in children is <0.1%. COVID-19 infection in children may present with anemia, thrombocytopenia, hypoalbuminemia, and altered INR [12]. Other laboratory abnormalities may include leukopenia, lymphopenia, increased transaminases and inflammatory markers such as procalcitonin and C-reactive protein [1, 16]. While patchy lesions in pulmonary lobules of children are identified on chest computed tomographic scans with moderate infection, the ground-glass opacities which are a typical feature in adults are rare in pediatric patients [15]. The mechanisms underlying the unique presentation of COVID-19 in children are unknown and further study is required to understand why the presentation differs in children.

IgA antibodies have been found both in Kawasaki disease and in COVID-19 cases with vasculitis. This suggests that MIS-C could be triggered by a COVID-19 infection and that similar to Kawasaki disease, IgA antibodies are produced. These antibodies have receptors in endothelial, mucosal, and cardiac cells [1]. This hypothesis that the vasculitis is mediated by IgA antibodies may explain the similarities between the two pathologies and the potential post-infectious origin [1].

Another common pathology associated with COVID-19 in children is "COVID toes", or chilblains. This primarily affects the toes but can also be seen in the heels and fingers, presenting as red-purple, tender, or itchy bumps [17]. The cause appears to be the result of vascular damage through the impact of the SARS-CoV-2 virus on endothelial cells as well as T-cells CD4, CD8, and B-cells [1].

#### **3.1 Multisystem inflammatory syndrome in children (MIS-C)**

While most cases of COVID-19 in children range from asymptomatic to mild/ moderate disease, severe disease has been documented in children. Some countries have documented cases of COVID-19 in children under the age of five [1, 18] with an acute inflammatory syndrome called Multisystem Inflammatory Syndrome in Children (MIS-C) [1, 3] that is similar to Kawasaki disease [1, 3, 19] that is a medium-vessel vasculitis [1, 18] and typically presents 2 weeks after initial infection. The most commonly affected vessels in MIS-C are the coronary arteries [20].

Most infants (more than 80%) infected with SARS-CoV-2 develop mild COVID-19 with a natural history similar to other self-limited respiratory viruses, without complications [21]. But in the case of children who develop MIS-C, severe systemic inflammation occurs with elevated pro-inflammatory cytokines and acute phase reactants, affecting multiple organ systems including the gastrointestinal, respiratory, cardiovascular, renal, hepatic, hematological and nervous systems among others [22, 23]. The most comprised organ systems include the gastrointestinal, dermatologic and cardiovascular organ systems.

MIS-C typically presents with fever lasting more than 4 days [1, 12, 16] as the universal characteristic. Gastrointestinal symptoms [1, 3, 12] may also present as the first symptoms [24]. These include abdominal pain, vomiting [1, 3, 12], and diarrhea [24]. Neurological symptoms such as headache, sensory disturbances, and meningeal signs [1, 24] can also be present. Hemodynamic instability can be present as well as cardiovascular complications including heart failure, myocarditis and pericarditis. Laboratory values may demonstrate elevations in troponin, proBNP, ferritin, C-reactive protein, and D-dimer with neutrophilia and lymphopenia [1, 12, 16]. Patients may also develop shock [1, 16] with single or multi-organ dysfunction requiring intensive care, mechanical ventilation [1, 12] and/or extracorporeal membrane oxygenation (ECMO) [3, 12]. Cytokine storm and ferritin counts >1400 μg/L may present in older patients [1]. In summary, MIS-C presents as a hyperinflammatory syndrome with gastrointestinal, neurologic and cardiac manifestations.
