Fifty-six children with MIS-C, hospitalised between October 1, 2020, and May 31, 2022, at the Buzzi Children’s Hospital in Milan, were followed up by a multidisciplinary team for 12 months following their admission to hospital. Our tertiary-care paediatric hospital was the referral hub for MIS-C in Lombardy, which was among the European regions hardest hit by the SARS-CoV-2 pandemic.

The multidisciplinary follow-up of these patients revealed no long-term effects on the heart and lungs, in agreement with the available literature [10, 20]; it also showed complete resolution of the neurological symptoms that characterised the clinical picture during hospitalisation [21]. By 6 months post-admission, there was already almost complete resolution of the clinical, laboratory, and instrumental abnormalities observed in the acute inflammatory phase, and by the end of the follow-up, these abnormalities had completely disappeared.

In contrast, we observed increased BMI values (e.g. increased adipose tissue) 6 months after the acute phase [22]. This finding is in agreement with literature reports [9, 11, 13].

Furthermore, at 12 months, a significant portion of children showed weight gain compared with their BMI at admission, as confirmed by increased BMI z-scores (Table 3). The finding of BMI z-score increases at 6 and 12 months after admission may be due to a lack of physical activity and/or to the presence of anxiety and/or depressive symptoms/emotional problems, factors that may reinforce each other and play a role in increasing BMI.

HOMA-IR index and TyG index were pathological in most of children during the acute phase. The release of a wide spectrum of cytokines, including IL-6 and tumour necrosis factor (TNF)-α, during the acute phase of MIS-C, leads to a systemic proinflammatory milieu [23]. Increased levels of IL-6 and TNF-α, in particular, are known to contribute to IR and b-cell hyperstimulation [24]. Despite of almost complete inflammatory biomarkers normalisation at mid- and long-term follow-up, HOMA-IR index and TyG index were found still abnormal in 31.1% and 71.4% of patients, respectively, at 6 months. Notably, the condition of IR persisted in about a third of the population at 12 months.

Of all the factors influencing the adverse effects of systemic glucocorticoids, dose and duration of therapy are the most important independent and well-documented risk factors [25]. Overall, it can be stated that prolonged exposure is a high-risk factor [26]. In regard to the long-term metabolic effects observed in our study, although the effects of systemic corticosteroids cannot be totally ruled out, it should be noted that only 20% of our patients were treated with high dose of systemic steroids, while we observed the persistence of IR in about one-third of patients. Moreover, metabolic adverse effects due to systemic corticosteroids are mostly associated with the long-term duration treatment (3 months or more) [27, 28]. Last, but not least, our patients were treated with systemic corticosteroids with intermediate biologic half-lives (e.g. methylpredinosolone and prednisone) that have lower potential for side effects than analogues do with long biologic half-lives (e.g. betamethasone) [29]. All these reasons make it unlikely that treatment with systemic corticosteroids may have influenced the long-term metabolic outcome in our study.

On the other hand, endocrine and metabolic system damage, directly or indirectly attributable to viral infection, seems to persist over time and to contribute to the long-term IR, as shown by preliminary data in our cohort [30].

The other sequelae observed in our patients can be grouped as signs and symptoms liable to affect general well-being. Problems of this kind were present at 6 months post-admission in the majority of patients and consisted mostly of a decline in adaptive functions, as shown by regressive behaviours, difficulty coping with usual school and play activities, fatigue, sleep problems, irritability, and excessive worrying about their health. About a fifth of the children also showed clinical repercussions, characterised by behavioural and emotional issues, and low QoL. This same clinical profile has already been observed and described in the first group of children treated at our hospital [12] and is confirmed by the present follow-up in the entire study sample. While the adaptive problems were resolved by 12 months in most of the children, the behavioural and emotional difficulties and low QoL, although rarer, persisted over time, with similar rates found between the 6- and 12-month assessments. Finally, it is noted that none of the children who were asymptomatic at 6 months developed symptoms during the remainder of the follow-up.

Our observations confirm the findings of other studies documenting the presence of emotional and behavioural problems in association with a lower QoL in children who presented MIS-C [13, 15]. It is possible that the experience of being ill and hospitalised might, in itself, explain, completely or in part, the appearance of this set of symptoms. Although this is still a new concept, recent evidence suggests that a severe and unexpected illness may act as a health risk factor when experienced by otherwise healthy individuals (of which children with MIS-C are but one example). In fact, a scenario of this type has recently been described in children hospitalised in intensive care. The “post-intensive care unit syndrome in paediatrics” developed by these subjects is defined as a constellation of cognitive, physical, and mental health impairments occurring after ICU admission, which may reflect changes in brain function (e.g. new-onset neurological morbidity) or in family dynamics, or physical changes [15, 31]. To further investigate this emerging concept, a structured follow-up protocol for children in the ICU has, in some countries, been introduced into national guidelines, the aim being to evaluate interventions designed to mitigate the risk of poor outcomes and therefore optimise the health of the child. In our sample, these impairments were observed both in children admitted to the ICU and in ones treated on regular wards; this, together with the fact that no correlation emerged with the length of ICU stay, seems to suggest that patients do not have to be admitted to the ICU in order to experience long-term effects of illness/hospitalisation on their psychological health and quality of life.

That said, although metabolic and psychosocial problems are relatively frequent 6 months after the physical and emotional destabilisation associated with the acute event, the majority of children had a positive long-term outcome, with no significant impact on their physical, mental, and social well-being. Nevertheless, at 1 year, a not negligible proportion still presented metabolic and emotional-behavioural alterations and a reduction in their QoL. Moreover, an overlap was found between the subset of patients with metabolic issues and those with problems liable to affect their general well-being and QoL.

To our best knowledge, this is the first study reporting long-term glycometabolic alterations, joined to persistent impairment in the realm of general well-being, behaviour, and decline in QoL, in a subgroup of children previously hospitalised with MIS-C.

Neither the severity of the inflammatory markers during the acute phase nor the duration of hospitalisation seems to be correlated either with the medium-term or with the long-term outcome. However, it remains conceivable that the acute illness per se may act as a trigger factor in a subgroup of predisposed subjects. MIS-C itself appears to develop in genetically predisposed individuals [32,33,34].

The presence of IR has been associated with neurocognitive impairments affecting, for example, executive functions and memory [35]. The endothelial dysfunctions caused by IR may result in blood–brain barrier breakdown, which in turn may allow proinflammatory molecules from the plasma to penetrate the CNS, thereby contributing to neuronal abnormalities and neuroinflammation [36]. Finally, the long-term sequelae of MIS-C may, in some subjects, also be due to the persistence SARS-CoV-2 in adipose tissue or other sites [37].

However, the mechanisms that might explain the long-term persistence of both metabolic alterations and neuro-behavioural outcomes and their possible relationship are far from being clarified.

Nevertheless, these findings highlight the possible impact of MIS-C on long-term health, understood not merely (or not so much) as the absence of disease or infirmity, but rather as physical, mental, and social well-being, in accordance with the WHO definition.

Our study has particular strengths, such as the presence of an MIS-C-dedicated multidisciplinary team which carried out serial and standardised clinical and instrumental assessments, and the fact that, since our centre served as a hub during the pandemic, we were able to collect a good-sized sample.

Weaknesses were the lack of a control group and the absence of a reliable pre-MIS-C well-being profile with which to compare the follow-up data relating to the psychological and emotional health, adaptive functions, and QoL of the enrolled children.

These findings point out to the potential long-term effects of pandemics and to the importance of a multidisciplinary follow-up to detect potential negative sequelae in different areas of health, both physical and psychosocial.

In particular, there is a need to have studies that examine the long-term effects of this complication on patients that have had MIS-C.