Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics

Background Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. Main body as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed. Conclusions we propose a document that will help physicians to diagnose and treat MIS-C patients. Given the level of evidence available and the methodology used, this document should not be interpreted as a guideline; the final decision about the optimal management should still be taken by the caring physician, on an individual basis.


Introduction
Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. To date, more than 943,000 cases have been diagnosed, with more than 41,192 deaths. Children accounted for around 2% of infections, with an estimated mortality rate of 0,2% [1]. These figures confirm the previous observation in China that children develop milder forms of the illness, compared to adults [2][3][4]. Nonetheless, there is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, which has been named Pediatric Multisystem inflammatory Syndrome temporally associated with COVID-19 (PIMS-TS) in the UK and Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C) in the US [5][6][7]. The latter term will be used in this paper. The clinical spectrum of MIS-C is wide, and children have been treated with a variable association of intravenous immunoglobulin (IV Ig), high-dose glucocorticoids, and anti-cytokine medications [8][9][10][11][12][13]. To date, although diagnostic and therapeutic recommendations have been proposed by various pediatric societies, no universally agreed approach is available [14,15].
After the first epidemic peak, which began in late February, the national lockdown policy in Italy led to a drastic reduction of cases, that, however, have restarted growing in the recent weeks. As MIS-C cases have been mostly observed in the regions with the highest impact of SARS-CoV-2 infection, we fear a recrudescence of the disease throughout Italy. We have, therefore, decided to prepare a report that helps clinicians to face this novel and challenging disease. Given the limited information currently available and the methodology employed, this document should not be seen as a guideline, but simply as a set of clinical suggestions based on the existing literature and the personal experience of the authors.

Case definition
There are multiple case definition criteria for MIS-C [16]. We propose to consider MIS-C diagnosis in the presence of: A child or adolescent with Fever (> 38°C) lasting for more than 24 h. + Signs/symptoms of at least 2 organs involvement a + Laboratory work-up showing systemic inflammation (leukocytosis with neutrophilia, ESR and CRP (and PCT) increase, with or without lymphopenia + Exclusion of infection b b a recent exposure to SARS-CoV2 may be demonstrated in the majority of patients by means of nasal/ pharyngeal swabs or serology. In case of high clinical suspicion, MIS-C diagnosis and treatment should not be delayed by a negative swab or serology. A personal history of close SARS-CoV contact is present in the majority of cases and may be sufficient to substantiate MIS-C hypothesis.  As many of the signs and symptoms listed are not specific, MIS-C diagnosis should rely on a high index of suspicion and cautious clinical judgement, taking into account the patient's history, the severity of organ involvement, the inflammatory markers level and other possible mimickers (Fig. 1).
LABORATORY WORK-UP

Treatment
To date, there is limited evidence to establish the optimal therapeutic approach to a child with MIS-C. Given the partial overlap of the clinical manifestations of MIS-C with those of Kawasaki disease, the majority of patients have been treated with the standard therapeutic protocols for the latter illness [17]. It is important to consider that the spectrum of clinical manifestations and severity of MIS-C is is wide. Thus, the best treatment approach should be defined on an individual basis, and the following proposals are to be interpreted only as suggestions.
Intravenous immunoglobulin 2 g/kg IV (up to 70-80 g) to be administered over at least 12 h. In patients with heart failure immunoglobulins should be administered over at least 16 h  Since MIS-C is a post-infectious disease, it is conceivable to assume that symptoms have their onset when the viremic phase is ended. Nonetheless, it is difficult to clearly differentiate these two phases (viremic vs hyperinflammatory) in some clinical scenarios. We recommend to consider carefully the appropriate timing to start immunomodulatory treatment in such cases, to avoid interference with antiviral host response.

Conclusions
Since there is a resurgence of COVID-19 cases throughout Italy, we expect a rise in MIS-C patients over the next weeks. Although MIS-C has variable severity, the majority of patients are seriously ill. The clinical experience indicates that prompt recognition and timely treatment are crucial to achieve good outcomes. Given the frequent overlap of clinical manifestations between MIS-C and Kawasaki disease, patients with the hyperinflammatory syndrome have generally been treated with the therapeutic protocols used in Kawasaki disease. Since the available information does not allow to formulate well-established guidelines or recommendations for MIS-C treatment, and the long-term sequelae of the illness are not yet known, we agree with the therapeutic regimens proposed and adopted so far. The final decision about the optimal management should be taken by the caring physician, based on the disease characteristics and severity of each individual patient.