In general terms, the clinical manifestations of SARS-CoV-2 infection are less severe in pediatric patients than in adults. The study published by Dong et al. revealed that only 6% of the more than 2,000 pediatric patients included, developed severe clinical symptoms , and only a small proportion needed intensive care. Respiratory problems are less frequent in children than in adults .
The occurrence of severe systemic hyperinflammatory symptoms probably associated with SARS-CoV-2 infection in children has raised concerns among scientific societies [14,15,16,17]. This syndrome, which symptoms mimic those of sepsis, KD or TSS, has been described in different studies [18,19,20,21,22,23,24,25,26,27,28,29]. The information available on the most severe manifestation of SARS-CoV-2 in children is also very limited [12, 36]. Our multicentric Registry identified the differences between PICU patients with symptoms of hyperinflammatory syndrome and those with SARS-CoV-2 infection without symptoms of hyperinflammation. To date large series of pediatric patients suffering severe manifestations of SARS-CoV-2 infection are lacking, and our study includes an important number of them. It is the first describing characteristics of SARS-CoV-2 infection comparing the patients presenting with multisystem inflammatory symptoms with those without.
Whereas the most of COVID-19 patients in the studies performed by Shekerdemian et al. and Sachdeva et al. in the USA and Canada [12, 36] had respiratory symptoms, inflammatory syndromes were more frequent in our series. This difference may be explained by the fact that Spain is in a more advanced stage of the pandemic, as no cases of this type were recorded in our Registry during the initial stages. Several studies in different regions have shown a delay between the peak of incidence of COVID-19 cases and the rise in the number of MIS-C cases [10, 21, 22, 27, 28]. In the same vein, the presence of previous comorbidities was higher in the sample of Shekerdemian et al. (above 80%), whereas previous comorbidities in our sample were only identified in patients without systemic inflammatory symptoms, who were prevailingly hospitalized during the first weeks of operation of the Registry. Many published studies point out that most patients presenting with MIS-C are previously healthy [19,20,21, 24, 26,27,28].
In total, 75% of pediatric patients with MIS-C were older than 6 years. This finding contrasts with KD, which is more frequent in children less than 5 years old . These findings are consistent with those observed in the studies published by Whittaker et al. and Verdoni et al. where MIS-C patients are compared with previous cohorts of KD patients showing older age [19, 22].
Cluster analysis has identified two big groups of patients in our cohort, those presenting with fever, shock, acute cardiac dysfunction, and gastrointestinal symptoms (the group of patients with MIS-C features), and a second group presenting with respiratory symptoms including ARDS that often associates also acute liver and kidney dysfunction (the group of patients with a more classical presentation of COVID-19).
In patients with MIS-C, gastrointestinal symptoms are more frequent than respiratory symptoms, whereas patients with SARS-CoV-2 typically show respiratory symptoms. This finding contradicts the data reported by Shekerdemian et al., who reported a very low incidence of gastrointestinal problems (2%) . In our series, gastrointestinal symptoms were uncommon in patients without MIS-C (4% of these patients have diarrhea), whereas more than 60% of patients with inflammatory syndromes exhibited gastrointestinal symptoms. This is in line with the previously described MIS-C case series, in which abdominal symptoms as abdominal pain, diarrhea, nausea and vomiting are present in most patients [10, 18,19,20,21,22,23,24, 26,27,28].
Fever is the most frequent symptom in patients with MIS-C, with 100% of patients developing a fever, whereas a third of the patients without MIS-C do not present a fever. Almost the totality of patients with MIS-C of our series exhibited arterial hypotension. It is worth noting that we only analyzed PICU patients. Therefore, there may have been patients with milder MIS-C symptoms who did not develop hemodynamic alterations and did not require intensive care as described in studies that include patients not requiring intensive care [19, 20, 22, 23, 27, 28].
As mentioned above, the clinical-laboratory manifestations of MIS-C mimic those of KD and TSS, and a high proportion of patients may meet the diagnostic criteria for both diseases [37, 38]. However, some of the typical symptoms of these diseases were very uncommon in our series, especially the typical cervical adenopathy of KD or the oral mucosa and lips lesions (only present in 1 out of 4 patients of our series) . Some studies have described how the presence of cutaneous manifestations in children with MIS-C might vary according the age, being less frequent in older patients [27, 28].
Concerning the laboratory parameters, the MIS-C patients presented severe inflammation, with very elevated levels of acute-phase reactants (CRP and PCT), exceeding those of SARS-CoV-2 patients without MIS-C. Although absolute leukocyte counts were not very elevated and were similar in the two groups, patients with MIS-C exhibited severe lymphopenia, with a high neutrophils/lymphocyte ratio and a low platelet count. Special attention needs to be paid to the fact that LDH was lower in patients with MIS-C as compared to those without MIS-C, since elevated LDH levels may be associated with hemolysis or myocardial damage. The clinical interpretation of this finding is challenging. The analytical findings in our series were similar to those previously reported, i.e., lymphopenia without significant leukocytosis, thrombocytopenia, and high CRP and PCT [18,19,20,21,22, 27, 28].
Hyperinflammatory state has been previously reported in adults presenting with COVID-19. This hyperinflammatory state has been related to disease severity and the need for mechanical ventilation and has been described in the context of classic COVID-19 syndrome presenting with bilateral pneumonia [39, 40]. In our study, contrary to the studies in adults, patients presenting with hyperinflammatory features such as elevated CRP, showed lower prevalence of chest x-ray abnormalities and lesser need of mechanical ventilation. Our study points out differences regarding hyperinflammatory states related to SARS-CoV-2 infection in children as compared to those described in adults. In adults, hyperinflammation is more frequent in the context of COVID-19 bilateral pneumonia and in children in patients with mild or absent respiratory symptoms presenting gastrointestinal symptoms and shock fulfilling MIS-C criteria.
Several authors have proposed a mechanism of immune dysregulation underlying MIS-C cases. In children, increased antibodies against receptor binding domain of SARS-CoV-2 have been described in patients with MIS-C compared with patients with COVID-19 without hyperinflammatory features . Activation of neutrophils and monocytes has been also described in the acute phase of pediatric patients with MIS-C with normalization in the resolution and convalescent phases of the disease . In adults with severe COVID-19, hyperinflammation and abnormal activation of different cell lineages have also been described widely . However, it remains unclear why in children, SARS-CoV-2 related hyperinflammatory states seems to affect more frequently cardiovascular and digestive organs instead of the lungs as seen in adults.
With regard to the treatments administered, most MIS-C patients admitted to the PICU required vasoactive therapy, whereas this therapy was less frequent in patients without this MIS-C. There was a high proportion of MIS-C patients requiring vasoactive drugs with conserved cardiac function and use of noradrenaline was also higher in this group. These facts might point out an important element of vasoplegia in MIS-C patients.
In contrast with the use of vasoactive drugs, the need of mechanical ventilation was higher amongst those patients without MIS-C. In overall terms, the use of mechanical ventilation nearly reached 30%, which is similar to the percentage reported in studies about PICU admissions including children with SARS-CoV-2 related diseases [12, 36]. In our population of patients with MIS-C, the use of mechanical ventilation was infrequent (below 15%) as described by Dufort et al. in New York State , and lower to the rates described in studies from other regions as U.S.A., U.K. and France where more than 30% of patients with MIS-C needed mechanical ventilation.
As to pharmacological treatments, most patients with MIS-C included in the Registry received antibiotic therapy. The use of immunomodulatory and corticosteroid treatments was also higher in the group of patients with MIS-C. No differences were observed in the use of antiviral treatments, although remdesivir was not administered to any of the patients with MIS-C. Remdesivir availability was limited in Spain during this phase of the pandemic. The distribution of remdesivir was subject to request and authorization by the ministry of health and administration in children was considered only in the context of a clinical trial. Remdesivir administration was requested in several patients in the MIS-C group but delay related to approval and favorable course in most MIS-C patients probably determined the difference in its use between groups. In view of the scant evidence available on the effectiveness of antiviral therapies in the treatment of SARS-CoV-2, further studies should be conducted to assess the efficacy of the immunomodulators used to treat similar symptoms to those described above (such as steroids and immunoglobulins) to attenuate the inflammatory mechanisms involved in the disease . Treatments used in patients with MIS-C are similar to those described in studies from other regions [21, 27, 28].
The relationship observed between time and the occurrence of MIS-C cases is worthy of note. All MIS-C patients were admitted to the PICU at least 15 days after the lockdown was imposed in Spain on March 15, 2020. In the stage where the first patients with MIS-C were recorded, in early April, the number of new cases was already decreasing. The simultaneous occurrence of similar symptoms to those described in our series in other European countries [18,19,20,21,22,23,24] leads us to foresee an increase in the incidence of this syndrome in more advanced stages of the epidemic in countries where the coronavirus spike occurred some weeks later than in Europe. This added to the fact that PCR was negative in more than half of MIS-C patients but serology was positive for SARS-CoV-2 in a high proportion of them 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 .
As to prognosis, the course of MIS-C patients included in our registry was generally favorable, without any mortality. Most patients were discharged to the ward in a few days. Other studies describe similar findings with low mortality in patients with MIS-C (below 3% in all series) [19, 21, 23, 24, 27, 28].
This study has some limitations. First, it is a multicentric study that includes most—but not all—PICUs in Spain. Therefore, some patients with similar symptoms could have not been included in the study. We consider that PICUs not participating in the registry do not represent a specific region or subset of PICUS that might prevent generalizing our results to all Spanish PICUs. Secondly, the new syndrome observed led us to retrospectively review the potential cases that may have been overlooked. Although the participating PICUs reviewed their records, some patients may have not been included. Although it is a prospective Registry, some clinical or laboratory variables were missing. Beside this, each hospital had their own microbiological tests and thus differences on diagnostic precision regarding SARS-CoV-2 infection might be present. As only patients admitted to PICU were included in the registry, we consider that probably our study does not include the whole spectrum of MIS-C and some patients might develop milder manifestations. Finally, the long-term course of patients could not be analyzed, given the short period of time elapsed from the onset of the clinical symptoms and analysis. In this sense, given that KD is one of the most frequent causes of heart disease acquired in childhood, it would be very interesting to describe the incidence of coronary lesions in patients with MIS-C.