ABSTRACT
Introduction: Multisystem Inflammatory Syndrome in children (MISC) was initially described during the first phase of COVID-19 pandemic as a severe clinical condition with systemic inflammation and multi-organ involvement. We previously published the results of the Italian multicenter survey of MIS-C, launched by the Rheumatology Study Group of Italian Pediatric Society We suggested that SARS-Cov- 2 might determine two types of inflammatory diseases in children: the classic KD, that could be triggered by the coronavirus, and the multisystem inflammatory syndrome, which has some specific clinical peculiarities. Objectives: The aim of our study was to analyze clinical features, laboratory findings and treatment strategies in patients diagnosed with MIS-C in Italy during SARS-CoV2 pandemic and evaluate if different outcomes may be related to different disease phenotype in order to establish specific prognostic criteria. Methods: This is an observational, retrospective, multicenter study. We enrolled the children hospitalized between September 1st 2020 and April 30th, 2021 with clinical diagnosis of multi-inflammatory syndrome (MIS-C). For each patient who received MISC diagnosis, we collected demographic, clinical, laboratory data, imaging findings, and treatment information in an online anonymized database (REDCap). We focused on the following main outcomes: the presence of heart abnormalities at dischargement, ICU admission, need of respiratory support or vasoactive agents and number of IVIG cycle administered analyzing a possible relationship with different disease phenotype. Results: 186 children were included in the study. The median age at presentation was 8 years (4-11), 103 (55%) patients were male and 83 (45%) female. 23 (12%) patients had pre-existing comorbidities. 130 (70%) patients presented a positive IgG serology for SARS-CoV-2 and 51% of patients reported a close contact. Markers of systemic inflammation at onset was elevated in all patients: CRP 143,2 mg/dl (111,0- 156,3), ESR 51,5 mm/h (51,0 -54,5), neutrophils 8200/mmc (6490-9011), D-dimer 2175 ng/ml (1076 - 2814). 16 (8%) children needed oxygen supplementation at baseline. 129 patients showed cardiac involvement characterized by myocarditis (23%), valve dysfunction (20%), hypotension (19%) and heart failure (15%). MAS was a complication in 11(6%) patients. ICU admission was required in 40 patients (22%). In our study, a majority of patients were treated with glucocorticoids (77%) and intravenous immunoglobulin (91%), of which 9% receveid two doses of IGEV. At dischargement heart ultrasonography showed valvular insufficiency (19%) and coronary abnormalities (8%). Conclusion: MIS-C has an extensive clinical spectrum that led to serious and life-threating illness. Systemic inflammation and specific organ involvement of cardiac and gastrointestinal involvement are the hallmarks. Good outcomes depends on prompt recognition and timely treatment, based on the combined use of glucocorticoids, high-dose immunoglobulins and anti-cytokine therapy.
ABSTRACT
Introduction: Multisystem inflammatory syndrome in children (MISC) is a severe and recently described disease affecting pediatric patients, triggered by SARS-CoV2. Current treatment is based upon IVIG and steroids but some patients are resistant to first line therapy. In these patients some authors have used IL1 receptor antagonist (Anakinra) with benefit, but data regarding efficacy, dose and route of administration are lacking. Objectives: To analyze the outcomes of MIS-C patients treated with anakinra (ANK) in Italy since 1/4/20. Methods: We performed an anonymous retrospective multicenter study of patients diagnosed with MIS-C, according to the preliminary WHO case definition, treated with ANK from 1/4/20 to 28/2/21. SARSCoV2 infection was demonstrated either by serology or by positive molecular swab (RT-PCR) in the six weeks prior to admission. After the start of ANK we measured the following outcomes: rate of patients needing further therapeutic step-up, rate of patients achieving clinical (fever defervescence in 24 hours) and laboratory response (CRP halving in 48 hours), rate of Coronary Artery Anomalies (CAA) development during follow-up. Results: In the study period 35 MIS-C patients were treated with ANK: 13 patients (37.1%) in Intensive Care Unit (ICU, Group A) and 22 (62.9%) in non-ICU settings (Group B). Epidemiological, clinical, and laboratoristic features at ANK prescription are described below: In Group A the most common indication for ANK was cardiac function worsening (46.1%), while in Group B ANK was started mostly for persistent elevation in inflammatory markers (ferritin, CRP) unresponsive to IVIG and/or steroids (31.8%). Endovenous (ev) ANK was used in all Group A patients (mean dose 8mg/Kg), while most patients in Group B (72.7%) received subcutaneous (sc) ANK (mean dose 4mg/Kg). Overall only 2 patients (5.7%) needed a step-up treatment after ANK start (1 required IVIG, 1 methylprednisolone dose increase), most of the patients achieved clinical (85.7%) and laboratory response (74.3%). 2 patients had CAA before ANK, none developed CAA after starting ANK. Overall NT-proBNP halved in 2.5 days in Group A and 2 days in Group B, while Ejection Fraction (EF) normalized respectively in 2 and 3 days. None of the patients in Group B needed ICU admission or inotropic support after ANK. The most frequently observed side effect was ALT increase (30.8% in Group A and 9.1% in Group B), only 1 patient had injection site reaction. Conclusion: MIS-C is a severe emerging disease with a high ICU admission rate. Our retrospective data suggest that both ev and sc ANK is effective in controlling inflammation, fever and cardiac dysfunction. Side effects are transient and usually mild. Overall the reported incidence of CAA in MIS-C cohorts is 10%, interestingly in our cohort no patient has developed CAA after beginning ANK, possibly suggesting a protective role of IL1 inhibition in aneurysm formation. Further studies in bigger cohorts are needed to define the most effective timing and dose of ANK in MIS-C.