Cardiac Implication in Pediatric Multisystemic Inflammatory Syndrome – Three Case Reports and Review of the Literature

The incidence of severe cases of SARS-CoV-2 infection in children is much lower compared to adults. However, the pediatric population may be severely affected by the onset of multisystemic inflammatory syndrome (MIS-C) which is related to immune dys-regulation occurring after the acute infection has passed. Pediatric multisystemic inflammatory syndrome (PMIS) associated with SARS-CoV-2 infection has similar symptoms to septic shock or Kawasaki disease.

The onset of delayed symptoms relative to the acute SARS-CoV-2 infection is variable. In children who have a well-known history of documented or suspected COVID-19, the usual duration between acute infection and onset of MIS-C symptoms is two to six weeks. However, rare cases of MIS-C occurring in more than 6 weeks after the acute SARS-CoV-2 infection have been reported¹.

The criteria used for case definition vary slightly between different health agencies. The case definitions of both the United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) are summarized in Table 1. According to WHO, the onset of a case with post COVID-19 multisystem inflammatory syndrome in children require all 6 criteria, as following: patient age under 19, persistent fever for more than 3 days, clinical signs of multisystem involvement (at least two of the following) – rash or bilateral non-purulent conjunctivitis, or mucocutaneous inflammation signs, hypotension or shock, features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities, evidence of coagulopathy, acute gastrointestinal symptoms, elevated markers of inflammation, no other obvious microbial cause of inflammation, evidence of COVID-19 (RT-PCR, antigen test, or serology positive), or likely contact with patients with COVID-19 (Table 1)².

Management strategies reported in the literature fall into 3 categories: (i) treatment of inflammation, (ii) treatment of shock, and (iii) thromboprophylaxis (Figure 1)³.

Figure 1

In Figure 2 we can see the treatment algorithm for children with multisystem inflammatory syndrome. Immunomodulatory treatment with high-dose intravenous immunoglobulin (IVIG) (2g/kg) in association with corticosteroids (Methylprednisolone 1 mg/kg/dose every 12 hours) is considered the first-line treatment. Current evidence supports the combination of Methylprednisolone with IVIG that work better than immunoglobulins given in monotherapy as first-line treatment. Resolution of fever and inflammatory markers can indicate the transition to oral steroids with gradually decreasing the doses in 2–6 weeks. Patients with toxic shock syndrome require inotropic support. The ideal inotrope remains to be decided by the clinician according to the clinical data, but there is a study that comments on the need to avoid Milrinone due to the counterproductive effect of peripheral vasodilation⁴.

Figure 2

The need for antiplatelet therapy depends on the presence of the coronary artery aneurysms or dilatation (Kawasaki-like disease may be associated). The need for anticoagulation of these patients is also discussed, in prophylactic rather than therapeutic dose (Figure 1).

The second-line of treatment depends on whether or not Kawasaki-like disease exists. If the presentation is most consistent with KD and there is failure of first line treatment, a second dose of IVIG associated with Methylprednisolone could be considered or Infliximab (a tumor necrosis factor - alpha inhibitor) may be used 3. In case of an inflammatory syndrome that does not meet the criteria of KD, then Tocilizumab - a recombinant humanized anti-IL-6 receptor monoclonal antibody may be used⁵. In addition to the immunosuppressive therapy, opportunistic infections treatment may be considered.

In children, the innate immune response acts earlier and promptly than in adults and this was considered as a “protective factor against SARS-CoV-2 infection in children”⁶. At the moment of reinfection with the same viruses, the immune response appears earlier and is more powerful due to memory cells^7,8,9. Another factor that may contribute to a lower susceptibility of children to coronavirus disease-2019 include the fact that children have fewer pro-inflammatory cytokines secretion than adults, and less lifetime exposure to toxins such as cigarette smoke and air pollution, factors which may affect the health of an individual's epithelium¹⁰.

In April 2020, the National Health Service in the United Kingdom alerted the medical community of children presenting critically ill with findings like Kawasaki disease (KD) or toxic shock syndrome in the setting of recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection¹¹. This syndrome was later referred to as pediatric multisystem inflammatory syndrome and multisystem inflammatory syndrome in children.

Initially, PMIS took place in clusters, occurring in approximately 4 weeks after the peak incidence of COVID-19 in heavily affected regions, initially in Western Europe and subsequently throughout North America. The initial report from England included 8 patients¹². Afterwards larger series were reported from France/Switzerland (35 cases), England (58 cases), multiple series from New York (33 cases, 17 cases) and across the United States (186 cases)^13,14,15,16. Most of the cases (79–95%) occurred in previously healthy children, with the most common preexisting comorbidities being asthma and obesity¹⁷.

In early stages of the pandemic, this disease was considered to be Kawasaki disease caused by COVID-19, because there are many symptoms of KD, such as rash, conjunctival congestion, chapped lips, and lymphadenitis. Although there are some phenotypic similarities between MIS-C and KD, there are still many differences between the two diseases, such as the age of onset for KD being less than 5 years old, and the median age in this study was over 5 years old. In KD, platelet count generally increased, while thrombocytopenia accounted for 26.42% of MIS-C cases. A systematic review of the literature published this year reported that gastrointestinal symptoms in KD and the degree of myocardial dysfunction are also rare, while myocarditis, coronary artery dilatation, cardiac systolic function affects, and gastrointestinal symptoms accounted for 35.97%, 17.83%, 56.32%, and 82.72% of cases, respectively, in MIS-C^18,19.

In our cases, clinical manifestations of PMIS have started with fever and gastrointestinal symptoms. These nonspecific symptoms at the time of disease onset can lead to misdiagnose this syndrome but after investigations were performed such as laboratory tests, echocardiography and screening of COVID-19 we could easily met all the diagnostic criteria.

We couldn’t establish the exact duration between the acute infection and onset of MIS-C symptoms because all patients had initial asymptomatic SARS-CoV2 infection, in fact all the affected children were previously healthy.

Laboratory tests (Table 2) showed leukocytosis (one case), neutrophilia presented in all cases and thrombocytopenia (one patient). All patients had significant increase in various inflammatory indicators such as C-reactive protein, procalcitonin, ferritin, interleukin-6 and, also, evidence of coagulopathy by increased levels of D-dimers.

In our study, all PMIS patients received IVIG at a dose varying between 0.5 and 2 g/kg as the first-line treatment. Because of shock or organ threatening event, methylprednisolone (1–2 mg/kg/day) was added to all patients (Table 3). To the refractory case number 1, high dose anakinra was given as the second-line treatment. Moreover, all the patients who had dilated coronary arteries received acetylsalicylic acid, initially, and for those with increased prothrombotic risk (elevated levels of D-dimers), anticoagulation therapy in prophylactic dose was added.

All patients had cardiovascular complications, as follows: coronary artery abnormalities, pericarditis, systolic or diastolic dysfunction which required inotropic support. All children received intravenous immunoglobulins and corticosteroids, treatment which seemed to improve symptoms and decrease inflammatory responses. Immunosuppressive therapy with Anakinra was needed only for the first patient because for the other two first-line treatment worked from the beginning. The average duration of hospitalization was 13.3 days. Aneurismal dilatation of the coronary arteries appeared only in the case of prolonged corticoid therapy (case 3), but implications and correlations are difficult to be concluded.

The multisystemic inflammatory syndrome may develop even after an asymptomatic SARS-CoV2 infection, all presented patients having positive SARS-CoV2 antibodies and no past history of infection.

Cardiac evaluation is mandatory in order to establish the type of cardiac implication with direct consequences to treatment. Immunomodulatory therapy, after IVIG and corticosteroid therapy may be needed, and the algorithm should be followed.

All patients need medium to long-term followed-up closely in order to elucidate the potential sequelae of this condition, including coronary aneurism with potential thrombosis and myocardial infarction.

Pediatric multisystem inflammatory syndrome may have a much more severe cardiovascular impact than acute SARS-CoV-2 infection. Most pediatric patients with postCovid-19 cardiovascular disease have a complete resolution of symptoms associated with PMIS.