Thrombotic Events in MIS-C Patients: A Single Case Report and Literature Review.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic hyperinflammatory disorder that is associated with a hypercoagulable state and a higher risk of thrombotic events (TEs). We report the case of a 9-year-old MIS-C patient with a severe course who developed a massive pulmonary embolism that was successfully treated with heparin. A literature review of previous TEs in MIS-C patients was conducted (60 MIS-C cases from 37 studies). At least one risk factor for thrombosis was observed in 91.7% of patients. The most frequently observed risk factors were pediatric intensive care unit hospitalization (61.7%), central venous catheter (36.7%), age >12 years (36.7%), left ventricular ejection fraction <35% (28.3%), D-dimer >5 times the upper limit of normal values (71.9%), mechanical ventilation (23.3%), obesity (23.3%), and extracorporeal membrane oxygenation (15%). TEs may concurrently affect multiple vessels, including both arterial and venous. Arterial thrombosis was more frequent, mainly affecting the cerebral and pulmonary vascular systems. Despite antithrombotic prophylaxis, 40% of MIS-C patients developed TEs. Over one-third of patients presented persistent focal neurological signs, and ten patients died, half of whom died because of TEs. TEs are severe and life-threatening complications of MIS-C. In case with thrombosis risk factors, appropriate thromboprophylaxis should be promptly administered. Despite proper prophylactic therapy, TEs may occur, leading in some cases to permanent disability or death.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Anticoagulation and Thrombotic Events in the Multisystem Inflammatory Syndrome in Children: Experience of a Single-center Cohort and Review of the Literature.

The multisystem inflammatory syndrome in children (MIS-C) is a severe clinical entity affecting the coagulative system; although thromboembolic events (TEs) are not common, most patients receive anticoagulation. We retrospectively assessed patients below 18 years admitted with MIS-C at Meyer Children's Hospital (Florence, Italy). Data on baseline clinical and laboratory presentation, treatment, and outcome, including differences between patients with and without thrombotic prophylaxis, were analyzed. Thirty-two children 1 to 15 years were included. Seventeen patients (53.1%) required intensive care admission, 2 (8.7%) had obesity, 7 (30.4%) a central venous catheter, and 14 (43.8%) an impaired cardiac function. Twelve patients (37.5%) received prophylactic anticoagulation: they had more frequent cardiac involvement (91.7 vs. 50%, P =0.02) and higher ferritin levels (median 1240 vs. 501.5 ng/mL, P <0.001). No differences were found in median d -dimers between the 2 groups. Twenty-one patients (65.6%) had d -dimers >5×upper limit of normal but the indication for anticoagulation was not driven by d -dimers. No patient had hemorrhagic events and only 1 patient (3.1%) had a superficial thrombotic event (under thromboprophylaxis). Our series and the available literature data on MIS-C and thromboembolic events suggest that TEs are a rare complication of MIS-C that is frequently associated with high d -dimer values. However, also in MIS-C, the well-established risk factors of pediatric TEs (ie, older age, central venous catheter, obesity, and cancer) should guide thromboembolic risk assessment.

Neuro-PIMS-TS: a single case report and review of the literature.

Neurological manifestations related to SARS-CoV-2 infection in adults have been largely reported since the beginning of the pandemic. Subsequent large-scale studies involving children confirmed the occurrence of neurological symptoms associated with SARS-CoV-2 infection also among paediatric patients, especially in the context of paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS). At this regard, we report the challenging case of a 10-month-old baby with PIMS-TS complicated by acute cerebral oedema successfully treated with intravenous immunoglobulins, corticosteroids and anakinra. Our results, combined with the evidence of larger case series suggest that higher inflammatory burden is more frequent in patients with neuro PIMS-TS. As regards neuroimaging, neuroimmune disorders are found to be more common during acute COVID-19, MERS is more frequent during PIMS-TS. Distinct immune mechanisms may underlie these different types of neurological involvement, which are yet to be understood. Further studies are required to better define the physiopathology of neuro PIMS-TS and its possible therapeutical implications.

Cardiac MRI in midterm follow-up of MISC: a multicenter study.

In this multicenter retrospective study we aimed to evaluate the outcome of cardiac involvement in children affected by multisystem inflammatory syndrome (MIS-C), assessed through cardiac magnetic resonance (CMR). Children referring to three Italian tertiary pediatric centers between February 2020 and November 2021 with a diagnosis of MIS-C, who underwent CMR during a follow-up visit, were enrolled. Demographic, clinical, laboratory, treatment, and outcome data were collected. Twenty MIS-C patients (aged 9-17, median 12 years) were included in the study. Heart involvement at onset was testified by hypotension/shock (55%), laboratory evidence of myocardial involvement (100%), reduced LV ejection fraction (EF) on echocardiography (83%), and/or need for inotrope agents (40%); they all presented good clinical, laboratory, and echocardiographic response to treatment. CMR was performed after a median interval of 3 months from discharge. Pericardial effusion and myocardial edema were found in 5% of patients. Mild residual left ventricular (LV) dysfunction was found in 20% of patients, all showing normal echocardiographic LVEF at discharge. Minimal myocardial scars were found in 25% by late gadolinium enhancement (LGE). One patient was evaluated at two consecutive time points, showing partial resolution of a myocardial scar after 7 months from its first finding. CONCLUSION: Despite the severity of heart involvement in the acute MIS-C phase, the mid-term cardiac outcome is good. Direct cardiac tissue viral invasion may be involved in MIS-C pathogenesis. WHAT IS KNOWN: • Heart involvement is common in MIS-C, but conflicting findings have been shown regarding cardiac outcome when assessed through cardiac MRI. WHAT IS NEW: • Midterm cardiac MRI shows mild abnormalities in patients recovered from MIS-C with any grade of severity of cardiac involvement at presentation.

Thromboembolic complications in children with COVID-19 and MIS-C: A narrative review.

COVID-19 and multisystem inflammatory syndrome in children (MIS-C) have been associated with a higher incidence of hypercoagulability and thromboembolic events (TEs), even in children, leading to relevant morbidity, and mortality. However, our understanding of such complications in childhood is limited. To better understand the incidence, clinical manifestations, risk factors, and management of COVID-19 and MIS-C-related TEs in children, a review of the current literature and a brief update on pathophysiology are given. Sixty-two studies, describing 138 patients with TEs associated with COVID-19 or MIS-C, were included. The overall number of TEs was 157, as 16 patients developed multiple TEs: venous TEs represented the majority (54%), followed by arterial thrombosis (38%, mainly represented by arterial ischemic stroke-AIS), and intracardiac thrombosis (ICT) (8%). Within the venous TEs group, pulmonary embolism (PE) was the most frequent, followed by deep venous thrombosis, central venous sinus thrombosis, and splanchnic venous thrombosis. Notably, 10 patients had multiple types of venous TEs, and four had both venous and arterial thrombosis including a newborn. Most of them (79 cases,57%) had at least one predisposing condition, being obesity the most frequent (21%), especially in patients with PE, followed by malignancy (9%). In 35% of cases, no data about the outcome were available About one-third of cases recovered, 12% improved at discharge or follow-up, and 6% had persistent neurological sequelae. The mortality rate was 12%, with death due to comorbidities in most cases. Most fatalities occurred in patients with arterial thrombosis. Pediatricians should be aware of this life-threatening possibility facing children with SARS-CoV-2 infection or its multisystemic inflammatory complication, who abruptly develop neurological or respiratory impairment. A prompt intensive care is essential to avoid severe sequelae or even exitus.

Early anti IL-1 treatment replaces steroids in refractory Kawasaki disease: clinical experience from two case reports.

Refractory Kawasaki disease (KD) is related to a major risk of coronary arteries abnormalities and its treatment is not standardized. In this regard, anakinra (ANA), an interleukin (IL)-1 receptor antagonist, represents an emerging therapeutic option. We report two cases of children, diagnosed with KD, nonresponsive to two doses of intravenous immunoglobulins, successfully treated with ANA, without a prior use of steroids. Patient 2 developed a coronary dilatation, that improved significantly after ANA therapy. Our experience highlights IL-1 blockade effectiveness in reducing KD inflammation and suggests ANA adoption as second-line therapy, with a timesaving and steroid-sparing strategy. Our results, combined with the evidence of the IL-1 key role in KD and coronary arteritis pathogenesis and to the recent clinical evidence reported by the KAWAKINRA trial, encourage an earlier recourse to ANA in patients with refractory KD, in order to fight inflammation, and to treat and prevent the development of coronary artery aneurysms. Further studies are needed to better define the place of IL-1 blockade in KD step-up treatment.

Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.

BACKGROUND: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. METHODS: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. RESULTS: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. 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 showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. CONCLUSION: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

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.