Cardiotoxicity represents the primary mechanism involved in the development of COVID-19 associated cardiac injuries and it is a multifactorial process involving the entry of the virus into cardiac cells due to the presence of ACE-2 on their surface as we already mentioned, COVID-19 associated hypoxia, and the side effects of the drugs used for this infection [20]. The direct viral invasion was sustained by previous studies which noticed the presence of viral RNA in 35% of the patients infected with other coronaviruses who died from myocardial infarction [20, 21, 22]. Based on the well-known children’s peculiarities related to the ACE-2 receptor distribution and the cellular viral invasion, we might explain the children’s lower susceptibility of developing severe forms of COVID-19 when compared to adults [23, 24].

The second most important mechanism is represented by the immune-mediated reactions secondary to the overproduction of cytokines or dysregulation of T cells triggered by the virus itself, both leading to endothelial dysfunction and microvascular damage [21, 25, 26, 27]. Moreover, the studies performed on animals pointed out that the increased level of cytokines along with the overproduction of inflammatory mediators might be involved in decreasing cardiac contractility via calcium-dependent pathways [28, 29, 30]. Another important role of the cytokine storm is related to the maintenance of hemodynamic instability due to their ability to cause peripheral vasodilation [28, 31, 32, 33, 34, 35]. In fact, this immune-mediated mechanism is the core of MIS-C and this hypothesis is sustained in several reports that mention complete recovery of the cardiac injuries after therapy with immunomodulatory agents such as intravenous immunoglobulins and systemic corticosteroids [10, 28, 29, 31, 33, 34, 36, 37, 38].

The procoagulant state caused by SARS-CoV-2 infection is another potential mechanism involved in the occurrence of cardiac lesions associated with this infection. Several studies and case reports proved that this virus has the ability to increase the risk of ischemic and thromboembolic events [5, 20]. This hypothesis is also sustained by similar effect of other coronaviruses that was proved in previous studies with a major impact on regulating the genes responsible for triggering a procoagulant state [20]. This procoagulant effect is the most expressed in patients previously diagnosed with congenital heart disease [29, 34, 37, 38]. Several studies from Italy and China highlighted that patients with preexistent cardiovascular disease, congenital or acquired have a higher risk of COVID-19-associated mortality [13, 39]. Unsurprisingly, in most of the cases this risk increases with the severity of congenital heart disease [40, 41]. Moreover, these patients usually present also with other organs affected due to their congenital malformations involving lung and renal disease, as well as cirrhosis which further increase the risk of developing severe COVID-19 forms [42]. Patients with congenital and acquired heart diseases need close monitoring since certain symptoms caused by either COVID-19 and their underlying disorders such as shortness of breath, fever and palpitation may overlap during the course of this infection indicating for example either an endocarditis or a severe form of COVID-19, and the cause of this symptoms should be carefully and early identified in order to prevent life-threatening complications [10, 43]. Disseminated intravascular coagulation was also proved to induce myocardial injury according to post-mortem biopsy reports of patients infected with coronavirus [44].

This procoagulant state is no longer a myth in pediatric patients at the beginning of this pandemic era, clinicians were forced to adjust their previous knowledge for this mysterious condition and therefore several reports mentioned using antiplatelet and/or anticoagulant drugs in patients with COVID-19 and increased risk of thromboembolic events such as giant coronary aneurisms or severe disease [45]. Moreover, the International Kawasaki Disease Registry recommended the use of prophylactic dosing of anticoagulants in patients $\ge$12 years of age with obesity, altered mobility, preexistent thrombophilia or history of thrombosis, as well as critical presentation of COVID-19 [45]. Later, the Advanced Cardiac Therapies Improving Outcomes Network, a collaborative network dedicated to improve the outcomes of children with end-stage heart failure [46] designed an algorithm for evaluation the risk of MIS-C thrombosis including echocardiogram, electrocardiography, baseline anticoagulation laboratory tests (complete blood count, renal and liver function), tests for characterizing the inflammatory status (ferritin, von Willebrand factor antigen, erythrocyte sedimentation rate and C-reactive protein), as well as tests for characterizing the coagulation profile (Prothrombin Time/International Normalized Ratio (PT/INR), D-dimer ever 24–72 hours during admission, partial thromboplastin time, fibrinogen, lactate dehydrogenase, platelet count, thromboelastographic with platelet mapping, and thorough anamnesis for detecting history of recent or remote thrombosis, as well as family of personal history of thrombophilia) [47]. According to the previously mentioned guidelines, all these investigations should be performed at admission and at discharged, but also if the clinical status changes.

In terms of thromboprophylaxis during admission, the authors stated that patients should continue their antiplatelet or anticoagulant treatment for their preexisting conditions in the setting of COVID-19. Moreover, for those without preexisting antiplatelet or anticoagulant therapies, aspiring should be used in all patients with MIS-C except for those with platelet count 100,000/mm${}^3$, fibrinogen 100 mg/dL, and those with active hemorrhage or high risk of bleeding [47]. The treatment should be administered at least one month or even longer if the laboratory tests remain modified. In addition to aspirin, the authors recommended full anticoagulation for patients with moderate or severe ventricular dysfunction, coronary dilation or aneurism defined by a z-score $\ge$10, as well as D-dimer $>$10x upper normal limit until the patient is able to switch to prophylactic dose as laboratory tests and echocardiogram parameters improve. Prophylactic dose of anticoagulant along with aspirin should be provided in patients with mild to moderate ventricular dysfunction, coronary dilation or aneurism with a z-score between 2.5 and 10, venous thromboembolism prophylaxis according to institutional recommendations, D-dimer between 5–10x the normal upper limit, electrocardiogram abnormalities or thromboelastographic maximal amplitude $\ge$80 mm. The prophylactic dose should be continued according to the underlying condition if present, and if not until the laboratory tests and echocardiography improves [47]. Antiplatelet and/or anticoagulant therapies should be continued for approximately 1 month after the diagnosis depending on the inflammatory and coagulation tests. Moreover, electrocardiogram and echocardiography should be repeated within 2 weeks after discharge if the patients was found with abnormalities during admission and serially thereafter until the normalization of modified parameters [47].

Taking into account the severity of cardiac lesions triggered by SARS-CoV-2 infection, the children associating these types of complications should definitely be considered with severe COVID-19 forms.

Several studies and case reports during the pandemic emphasized that young age might be considered a major risk factor for severe COVID-19 [48]. Thus, two multicenter studies performed on COVID-19 children from Europe pointed out that neonates are more likely to require intensive care unit (ICU) admission as compared to older children [49, 50]. Similarly, two case series also concluded that neonates have a higher risk of developing severe forms of COVID-19 [51, 52]. Nevertheless, the results remain controversial since other studies involving children below the age of 1 and 2 years revealed a lower prevalence of severe COVID-19 when compared to other age groups [53, 54]. Moreover, other authors also failed in identifying a significant association between neonates and the risk of ICU admission due to COVID-19 [55, 56]. A recent systematic review concluded that age does not impact the severity of COVID-19, but in terms of neonates subgroup the authors found a higher risk of severe COVID-19 as compared to other groups [48].

Prematurity, immunocompromised status and several underlying conditions such as genetic syndromes, neurological disorders, chronic lung disease, asthma, diabetes and obesity were also reported to contribute in certain cases to the development of severe COVID-19. Prematurity seems to have a great impact on the occurrence of severe forms triggered by SARS-CoV-2 infection. A study performed on COVID-19 children from the United Kingdom showed a prevalence of ICU admission of 19.2% in premature infants as compared to only 6% in full-term ones [50]. Similar findings were reported also for United States of America [57]. Immunocompromised patients were also reported to be at risk for developing severe COVID-19 [48]. In terms of immunocompromised status, children with oncological disorders seem to have the greatest chance for requiring ICU admission [58]. Moreover, those with hematopoietic stem cell transplantation were also proved to have an increased risk of severe COVID-19 [59]. Likewise, neurological disorders might also worsen the clinical course of COVID-19 in children, especially if they were previously diagnosed with seizure disorders [48]. A previous case reported by our team with a history of neurological disorder associating seizures also required ICU admission due to COVID-19 and unfortunately presented a fatal outcome [5]. Chronic lung diseases displayed the same negative impact on the severity of COVID-19 as the previously mentioned comorbidities [48]. Contrariwise, asthma seems to not influence either the clinical course or COVID-19 or the need for ICU admission in children [48, 50, 60, 61]. Children with type I diabetes mellitus were also proven to develop more severe forms of COVID-19 during the pandemics, but they did not necessarily require ICU admission [48, 50, 56, 57]. As compared to aforementioned controversial factors, obesity was found constantly to have a negative impact on the clinical course of this novel condition leading to severe COVID-19 forms in pediatric patients [48]. These findings were supported by both studies performed at the beginning of COVID-19 pandemics [50], and the recently published ones which after assessing for large samples of children (4302 COVID-19 children from USA) concluded that obesity associated an increased risk of severe forms requiring ICU admission and respiratory support, increasing at the same the mortality rate in young ages [57]. Similar findings were reported also by our team highlighting an association between obesity and the occurrence of MIS-C in a pediatric patient [4]. Contrariwise, genetic pathologies such as chromosomal abnormalities, congenital anomalies, and genetic disorders seem to have no impact on the occurrence of severe disease in COVID-19 pediatric patients, if not associated with other comorbidities [48].

Although there is a paucity regarding longitudinal data on COVID-19-associated cardiac injuries in pediatric patients, a recent study involving 60 controls and 60 patients with MIS-C assessed cardiac outcomes at 3–4 months after the onset of this condition based on both echocardiography and cardiac magnetic resonance findings [101]. The authors concluded that functional myocardial recovery and coronary outcomes are usually good in children with multisystem inflammatory syndrome triggered by SARS-CoV-2 underlining the absence of persistent subclinical dysfunction according to the used sensitive deformation parameters.