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Background and Aim: Cardiac involvement in multisystem inflam-matory syndrome in children (MIS-C) associated with Coronavirus 2019 disease (COVID-19) is often observed with high risk of hearth failure. Early diagnosis and treatment are man-datory for a good outcome. The aim is to describe cardiovascular involvement, management and early outcome for patients with MIS-C and to analyze the differences in cardiovascular manifesta-tions between two groups: younger and older than 6 years old. Method(s): This retrospective observational study describes cardio-vascular clinical manifestations, laboratory findings, cardiac imag-ing, according to different age groups, and treatment in patients with diagnosis of MIS-C admitted to the Pediatric Istitute Giannina Gaslini between March 2020 and September 2021. Result(s): We collected 25 patients. Median age at onset of symptoms was 5 years old (interquartile range IQR, 3-12 y), 12 boys (56%). Immunoglobulin G antibodies were positive in 70% cases, Polymerase chain reaction (PCR) nasal/throat swab test for COVID-19 was positive in 15% cases, at the admission. The remaining cases had close contacts of COVID-19 positive cases. Predominant coronary artery abnormalities were observed in age group up to 6 years old (n.13) with development of small and medium aneurysms in half of cases and low rate of mild ventricular dysfunction. While children between 7-18 years of age present myopericardial involvement with ventricular dysfunction in 67% cases, from mild to moderate. Only two cases of transient coronary dilatation. Frequent electrocardiogram abnormalities: ventricular repolarization anomalies and reversibile QTc prolon-gation interval. Laboratory findings showed rised inflammatory markers and only mild elevation of cardiac enzymes compared to an early and significant NT-pro-BNP increase. All patients were treated with intravenous immunoglobulin and corticosteroids. Some cases needed anakinra. Aspirin and heparin was adminis-trated. No inotropes requied but only cardioprotective therapy. No need of Intensive Care Unit. Conclusion(s): This case-series shows the frequent cardiovascular involvement in MIS-C with a peculiar distribution, according to differents age's group: coronary artery anomalies in young ones, myopericardial disease in old ones. Prompt multi target anti-inflammatory therapy could have an effect to favorable outcome.
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Introduction: COVID-19 severe pneumonia has been associated to systemic inflammation and elevation of blood parameters and reminiscent of cytokine storm syndrome. Stimulation of PBMC from patients with severe COVID-19 have shown a high secretion of IL-1β, a pivotal cytokine driving inflammatory phenotypes, which maturation and secretion is regulated by NLRP3 inflammasome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients, however the mechanisms by which SARS-CoV2 virus triggers such an extensive inflammation remain unexplained. Objectives: The overall objective of this study was to investigate if SARS-CoV2 drives inflammation in COVID-19 patients through NLRP3 inflammasome activation and IL-1β secretion. Methods: Samples from SARS-CoV2 infected patients, were collected at day 0 and at 3 and 7 following treatment with anakinra. Fresh monocytes, purified through adherence, were cultured for 3, 6, 18 h in the presence or absence of LPS (100 ng/ml) and MCC950 (10μM). Release of IL-1β, IL-1Ra, IL-6, TNF-α, IL-18 was quantified by ELISA kit. Relative gene expression analysis of ORF3a gene was performed by RT-qPCR. THP-1 cells were transfected with a plasmid containing ORF3a sequence by nucleofection. NLRP3 inflammasome and ASC speck formation were detected by confocal microscopy and/or by FACS analysis. Results: In the present study we show that circulating monocytes from COVID-19 patients display ASC specks, index of NLRP3 activation, and spontaneously secrete IL-1β in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV2 protein, resulted in NLRP3- dependent ASC speck formation. The involvement of ORF3a in inflammasome activation was further supported by the detection by RT-PCR of ORF3a in monocytes from COVID-19 patients. Conclusion: In summary, these results provide a mechanistic explanation for the strong inflammatory manifestations associated to COVID-19 and further evidence that NLRP3 and IL-1β targeting could represent an effective strategy in this disease.
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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.
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Introduction: By now, most of the children with COVID-19 infection have only mild symptoms. However, in the past year a small number of children have developed a serious inflammatory condition in temporal association with COVID-19 pandemic. This condition, named Multisystem Inflammatory Syndrome in Children (MIS-C), is characterized by a systemic inflammation with multiorgan failure;the clinical and laboratory features are similar to those usually observed in Kawasaki disease, cytokine storm syndrome and macrophage activation syndrome. While the SARS-CoV-2 PCR on nasal swab is positive only in a minority of patients, the serology is positive in most of them. Objectives: to create an International multicenter collection of patients with MIS-C involving the main pediatric networks committed in the care of patients with hyperinflammatory conditions. Primary endpoint of the project is to collect information on clinical presentation, laboratory parameters, clinical outcome and response to treatment of patients with MIS-C. Secondary endpoints of the project are: 1) to analyse different clusters in clinical phenotype in relation to age and geographical location, 2) to identify clinical and laboratory predictors of disease severity and outcome, 3) to evaluate the availability of samples of patients in the repositories linked to the different centers. Methods: a steering committee constituted by representatives of ERN-RITA, PRES, ESID and ISSAID and with the coordination of PRINTO developed a shared form to collect clinical manifestations, laboratory features, response to treatment and outcome of patients with MIS-C. The registry is available online on PRINTO website (www.printo.it). Results: a first survey between centers members of PRINTO network identified 365 patients from 51 centers (43 countries). Currently, 180 patients have been enrolled in the registry from 25 centers worldwide. Moreover, 11 additional centers have been activated and are ready to start enrollement. Ethical committee submission or activation procedures are ongoing in 36 more centers. 31 European countries and 12 extra-European countries are actively involved. Conclusion: After some interesting national initiatives, the HyperPEDCOVID registry will give the chance to analyze the impact of Multisystem Inflammatory Syndrome Children at the European and extra- European level, giving the possibility to analyze the distribution, clinical presentation and long-term outcome of this condition in different countries. The registry can also represent the basis for further biological and genetic studies in these patients.
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Introduction: Italy was affected by the SARS-CoV-2 epidemic after its outbreak in China. With a 4-weeks delay after the peak in adults, we observed an abnormal number of patients with characteristics of a multi-inflammatory disease and similarities with Kawasaki Disease (KD). Others reported similar cases, defined PIMS-TS or MIS-C.1,2 Objectives: To better characterize clinical features and treatment response of PIMS-TS and to explore its relationship with KD. Methods: We conducted an observational, retrospective, multicenter study. On April 24th-2020 the Rheumatology Study Group of the Italian Pediatric Society launched a national online survey, to enroll patients diagnosed with KD or with a multisystem inflammatory disease between February 1st 2020 and May 31st. The population was then divided into two different groups: 1) Classical and incomplete KD, named Kawasaki Disease Group (KDG);2) KD-like multi-inflammatory syndrome, named KawaCOVID (KCG). An expert panel of pediatric rheumatologists re-analyzed every single patient to ensure appropriate classification. Data were collected with an online database. Results: 149 cases were studied, 96 with KDG and 53 with KCG. The two population significantly differed for clinical characteristics (see table 1). Lymphopenia, higher CRP levels, elevated Ferritin and Troponin-T characterized KCG such as lower WBC and platelets (all p values<0,05). KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%;p=0.04 and 71,9% vs 43,4%;p=0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%;p<0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%;p<0.0001). Short-term follow data on KCG showed minor complications while on KDG a majority of patients had persistence of CAA. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data between the two groups Conclusion: Our study would suggest that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD, possibly triggered by SARS-CoV-2, and PIMS-TS. Older age at onset and clinical peculiarities, like the occurrence of myocarditis, characterize this multiinflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.