Serum endocan (ESM-1) as diagnostic and prognostic biomarker in Multisystem inflammatory syndrome in children (MIS-C).

Endothelial-cell-specific molecule-1 (ESM-1) also called endocan is a well-known biomarker for detecting inflammation, endothelial dysfunction (ED), and cardiovascular (CV) risk in COVID-19 patients. Upon SARS-CoV-2 infection, a small percentage of children develop Multisystem Inflammatory Syndrome in children (MIS-C). Whether endocan can be used as a biomarker of MIS-C is unknown. In this study, we assessed ESM-1 levels in MIS-C (n = 19) and healthy controls (HC; n = 17). We observed a significant increase in serum ESM-1 levels in MIS-C vs HC (p = 0.0074). In addition, ROC curve analysis demonstrated that this factor has a reasonable discriminatory power between MIS-C patients and HC (AUC of 0.7585). Notably, after one week of hospitalization and care, ESM-1 levels decreased, and this reduction was observed also for other inflammatory and pro-thrombotic markers like C-reactive protein, procalcitonin, fibrinogen, D-dimer, and ferritin, suggesting a general recovery trend in MIS-C patients. In fact, we observed that serum ESM-1 levels positively correlated with procalcitonin (PCT) (r = 0.468; p = 0.043). Finally, logistic regression analysis demonstrated an association between endocan levels and cardiac complications like myocarditis. Therefore, this study suggests that ESM-1 is a valuable diagnostic and prognostic biomarker in patients with MIS-C that may help identify those MIS-C patients at higher risk for cardiovascular complications and guide treatment strategies.

Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With COVID-19 Infection in Morocco.

Introduction. This study aims to describe the clinical and paraclinical characteristics of Multisysteminflammatory syndrome in children (MIS-C). Methods. A retrospective study encompassing 52 children diagnosed with MIS-C according to the World Health Organization criteria, over a 3-year period at Abderrahim Harrouchi Hospital in Morocco. Results. The median age was 6 years (IQR: 1-14), with a sex ratio of 1.16 (28 boys and 24 girls). Clinical manifestations were predominantly characterized by fever in all cases (100%), respiratory and gastrointestinal symptoms in 30 cases (58%) and 23 cases (44%) respectively, and shock in 9 cases (17%). We noted a myocarditis in 6 cases (12%). The treatment comprised intravenous human Immunoglobulin combined with methylprednisolone in all patients (100%). Conclusion. The characteristics of our MIS-C patients were similar to those in the literature, but more studies are needed to confirm these results.

Altered Spike Immunoglobulin G Fc N-Linked Glycans Are Associated With Hyperinflammatory State in Adult Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome in Children.

Background: Severe coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome (MIS-C) are characterized by excessive inflammatory cytokines/chemokines. In adults, disease severity is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G (IgG) Fc afucosylation, which induces proinflammatory cytokine secretion from innate immune cells. This study aimed to define spike IgG Fc glycosylation following SARS-CoV-2 infection in adults and children and following SARS-CoV-2 vaccination in adults and the relationships between glycan modifications and cytokines/chemokines. Methods: We analyzed longitudinal (n = 146) and cross-sectional (n = 49) serum/plasma samples from adult and pediatric COVID-19 patients, MIS-C patients, adult vaccinees, and adult and pediatric controls. We developed methods for characterizing bulk and spike IgG Fc glycosylation by capillary electrophoresis and measured levels of 10 inflammatory cytokines/chemokines by multiplexed enzyme-linked immunosorbent assay. Results: Spike IgG was more afucosylated than bulk IgG during acute adult COVID-19 and MIS-C. We observed an opposite trend following vaccination, but it was not significant. Spike IgG was more galactosylated and sialylated and less bisected than bulk IgG during adult COVID-19, with similar trends observed during pediatric COVID-19/MIS-C and following SARS-CoV-2 vaccination. Spike IgG glycosylation changed with time following adult COVID-19 or vaccination. Afucosylated spike IgG exhibited inverse and positive correlations with inflammatory markers in MIS-C and following vaccination, respectively; galactosylated and sialylated spike IgG inversely correlated with proinflammatory cytokines in adult COVID-19 and MIS-C; and bisected spike IgG positively correlated with inflammatory cytokines/chemokines in multiple groups. Conclusions: We identified previously undescribed relationships between spike IgG glycan modifications and inflammatory cytokines/chemokines that expand our understanding of IgG glycosylation changes that may impact COVID-19 and MIS-C immunopathology.

Myocardial deformation in multisystem inflammatory syndrome in children: layer-specific cardiac MRI insights from a pediatric cohort.

BACKGROUND: Multilayer strain magnetic resonance imaging (MRI) analysis offers detailed insights into myocardial mechanics and cardiac function by assessing different layers of the heart muscle, enabling a comprehensive understanding of cardiac involvement. OBJECTIVE: This study aims to explore cardiac strain differences between patients with multisystem inflammatory syndrome and a control group at medium-term follow-up, utilizing a layer-specific cardiac magnetic resonance imaging (CMR) approach. MATERIALS AND METHODS: In this retrospective study, patients with multisystem inflammatory syndrome in children (MIS-C) and a group of controls who had undergone cardiac magnetic resonance (CMR) imaging were selected and included. CMR was performed 30 days after discharge (range 34-341 days) for MIS-C patients. TrufiStrain research prototype software (Siemens Healthineers AG, Erlangen, Germany) was used for automated myocardial segmentation and strain calculation, to measure radial strain (RS), circumferential strain (CS), and longitudinal strain (LS) at the epicardial, mid-wall, and endocardial levels. Statistical analysis included Shapiro-Wilk tests, Student t-tests, and Mann-Whitney U tests, ANOVA, and regression analysis, maintaining a significance level of α = 0.05. RESULTS: The study cohort consisted of 32 MIS-C patients (≤ 18 years; 14 females) and 64 control participants (≤ 18 years; 24 females). Median interval to CMR post diagnosis was 142 days (range 34-341) with normal CMR findings for all patients. The mean age of the two groups was similar (MIS-C: 14.2 years; controls: 14.1 years, P = 0.49). There were no significant differences in height (MIS-C: 164.7 cm; controls: 163.9 cm, P = 0.84), weight (MIS-C: 68.2 kg; controls: 59.4 kg, P = 0.11), or body surface area (MIS-C: 1.7 m2; controls: 1.7 m2, P = 0.41). Global strain measurements showed no significant differences between the groups (global LS MIS-C patients - 16.2% vs - 15.7% in controls (P = 0.23); global RS 27.8% in MIS-C patients vs 29.5% in controls (P = 0.35); and global CS - 16.7% in MIS-C patients vs - 16.8% in controls (P = 0.92)). Similarly, layer-specific strain analysis across the endocardial (LS values of - 17.7% vs - 16.8% (P = 0.19), RS of 23.1% vs 24.8% (P = 0.25), and CS of - 19.9% vs - 19.9% (P = 0.92)), epicardial (LS - 14.9% vs - 14.5% (P = 0.31), RS of 31.2% vs 33.1% (P = 0.29), and CS of - 14.1% vs - 14.2% (P = 0.75)), and midmyocardial (LS - 16.5% vs - 16.3% (P = 0.18), RS 29.3% vs 31.8% (P = 0.31), and CS - 17.0% vs - 17.2% (P = 0.95)) levels revealed no significant disparities. The only notable finding was the reduced apical radial strain in MIS-C patients compared to controls (global RS MIS-C 12.4% vs 17.4% in controls, P = 0.03; endocardium RS MIS-C 4.9% vs 10.31% in controls, P = 0.01; epicardial RS MIS-C 17.7% vs 22.6% in controls, P = 0.02; and midmyocardium RS MIS-C 12.5% vs 17.9% in controls, P = 0.02). CONCLUSION: This study demonstrates that MIS-C does not significantly impact global or layer-specific myocardial strain values, as assessed by CMR, compared to a control group. The lower apical radial strain in MIS-C patients indicates a potential localized myocardial involvement.

Cytokine landscape in hospitalized children with multisystem inflammatory syndrome.

The etiology of multisystem inflammatory syndrome in children (MIS-C), frequently observed following COVID-19 infection, remains elusive. This study unveils insights derived from cytokine analysis in the sera of MIS-C patients, both before and after the administration of intravenous immunoglobulin (IVIG) and glucocorticosteroids (GCS). In this study, we employed a comprehensive 45-cytokine profile encompassing a spectrum of widely recognized proinflammatory and antiinflammatory cytokines, as well as growth factors, along with other soluble mediators. The analysis delineates three principal cytokine-concentration patterns evident in the patients' sera. Pattern no.1 predominantly features proinflammatory cytokines (IL-6, IL-15, IL-1ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor α (TNFα), C-X-C motif chemokine ligand 10 (CXCL10/ IP-10), and IL-10) exhibiting elevated concentrations upon admission, swiftly normalizing post-hospital treatment. Pattern no. 2 includes cytokines (IL-17 A, IL-33, IFNγ, vascular endothelial growth factor (VEGF), and programmed death ligand (PD-L1)) with moderately elevated levels at admission, persisting over 7-10 days of hospitalization despite the treatment. Pattern no. 3 comprises cytokines which concentrations escalated after 7-10 days of hospitalization and therapy, including IL-1α, IL-1ß, IL-2, IL-13, platelet-derived growth factor AA/BB (PDGF AA/BB). The observed in cytokine profile of MIS-C patients showed a transition from acute inflammation to sustaining inflammation which turned into induction of humoral memory mechanisms and various defense mechanisms, contributing to recovery.

Cardiology Consult for the General Pediatrician after Cardiac Manifestations from a SARS-CoV-2 Infection.

The novel Coronavirus Disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, created a need for evidence-based guidelines for the evaluation, management, and follow-up after infection. Data have become rapidly available, creating a challenge for medical providers to stay abreast of the ever-evolving recommendations. This document, written collaboratively by pediatric cardiovascular experts, pediatricians, and sports medicine specialists, is focused on SARS-- CoV-2-related pediatric cardiac manifestations. It aims to provide a systemic review of high-yield literature related to all cardiovascular entities as a tool for primary pediatric clinicians to utilize as they consider the cardiac consequences of acute SARS-CoV-2 infection, MIS-C, vaccine-related myocarditis, return-to-play, and long COVID-19 syndrome.

COVID-19 venous thromboembolism prophylaxis guidelines in pediatrics.

INTRODUCTION: SARS-CoV-2 (COVID-19) infection and multisystem inflammatory syndrome in children (MIS-C) are risk factors for venous thromboembolism (VTE). Guidelines for VTE prophylaxis were established at our institution at the beginning of the pandemic. Patients who had any VTE risk factors in addition to COVID-19 met criteria for anticoagulation prophylaxis. Patients who were diagnosed with MIS-C met criteria regardless of additional risk factors. MATERIALS AND METHODS: We conducted a retrospective review of patients admitted with COVID-19 or MIS-C to determine compliance with VTE prophylaxis guidelines and to evaluate the incidence of VTE and bleeding events in our population. RESULTS AND CONCLUSIONS: Among a total of 678 patients admitted with COVID-19 or MIS-C, 519 (76 %) patients met criteria for VTE prophylaxis and 348 (65.6 %) started prophylaxis. Logistic regression analysis identified a personal or family history of thrombosis or thrombophilia, diagnosis of MIS-C, admission to the intensive care unit, and presence of a central venous catheter as significantly associated with starting VTE prophylaxis. There were 18 patients who developed VTE. Minor bleeding events occurred in 19 patients (5 %), patient important bleeding, no intervention occurred in 8 patients (2 %), clinically relevant nonmajor bleeding in 8 patients (2 %), and major bleeding in 10 patients (3 %). The incidence of VTE in our patients with COVID-19 and MIS-C is similar to VTE rates at other institutions. We found that universally recognized VTE risk factors were appropriate to include as risk factors for thrombosis in hospitalized children with COVID-19 and MIS-C.

A Study of Hydroelectrolytic and Acid-Base Disturbances in MIS-C Patients: A Perspective on Antidiuretic Hormone Secretion.

COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) is a rare autoimmune disorder characterized by a range of polymorphic manifestations, similar to but distinct from other well-known inflammatory syndromes in children. We conducted a retrospective-descriptive study in which we summarized the clinical presentation of, biomarker variations in, and complications occurring in patients diagnosed with MIS-C, admitted to the Emergency Clinical Hospital for Children "Sf. Ioan", Galati, between July 2020 and June 2024. A total of 36 children met the MIS-C classification criteria according to the WHO-approved case definitions. A total of 41.7% (n = 15) were male and 58.3% (n = 21) were female. The median age of the study group was 4 years (IQR: 1.75-9.25 years). Surgical involvement was suspected in 16.7% (n = 6) of the patients, while 52.8% (n = 19) required intensive care. Clinically, fever was the most common symptom present in 89% (n = 32) of the cases. Gastrointestinal disorders were also common, with 50% (n = 18) presenting with inappetence, 42% (n = 15) with vomiting, and 39% (n = 14) with abdominal pain from admission, which worsened over time. Paraclinically, all patients exhibited signs of inflammation, and 86.1% (n = 31) had hydroelectrolytic and acid-base imbalances. The median hospital stay was 10 days (IQR: 7-12 days), with a stagnant clinical course in most cases. The inflammatory mechanisms in MIS-C, which can affect the secretion of antidiuretic hormone (ADH), were correlated with hydroelectrolytic disturbances and may lead to severe complications. For this reason, it is imperative to evaluate hydroelectrolytic disorders in the context of MIS-C and use diagnostic and prognostic biomarkers to develop effective therapeutic management strategies, ultimately improving the quality of life of affected children.

COVID-19-Associated Neurological Complications in Children.

Objectives: Neurological manifestations of Severe Acute Respiratory Syndrome coronavirus-2 have been well documented in adults during and after infection with the virus as well as after vaccination. The incidence of severe neurological symptoms among children is very low. This study aimed to analyze the varied neurological manifestations after COVID-19 infection among children and give a report on a single-center experience with these severe neurological symptoms. Materials & Methods: Case records of patients less than 18 years admitted between July 2021 to December 2022 with neurological manifestations and COVID-19 infection or with elevated COVID-19 antibodies after exclusion of other etiological diagnosis were analyzed. Results: There were 10 cases in the age range of 1-15 years. All the cases had elevated COVID-19 antibodies with history of contact 2-3 weeks prior except one who was positive for COVID-19 infection. Two cases presented with acute ascending paralysis suggestive of Guillain-Barre syndrome. Four cases presented with features of encephalopathy with clinical presentation fulfilling the criteria of Multisystem inflammatory syndrome in children. One case presented with fever and focal seizures with MRI showing sagittal sinus thrombosis, and one presented with fever and altered sensorium with MRI showing leukoencephalopathy. One child had cerebral mucormycosis without any evidence of immunosuppression. There was one child with features of encephalopathy with active COVID-19 infection. Conclusion: The varied presentation highlights the central and peripheral nervous system involvement by the virus in the pediatric population. It also emphasizes the need to investigate for COVID-19 in children presenting with these complaints during the pandemic.

Differentiating Multisystem Inflammatory Syndrome From Neonatal Sepsis: A Case Report.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits a spectrum of clinical manifestations, spanning from asymptomatic carriage to fatal outcomes. Among young infants, the incidence of severe disease is notably high. The pathogenesis of multisystem inflammatory syndrome (MIS) in neonates associated with SARS-CoV-2 remains elusive, although post-infective immune dysregulation is posited as a significant contributor. Recent cohorts have highlighted the transplacental transfer of immunoglobulins, potentially exacerbating immune dysregulation due to the co-transfer of inflammatory cytokines. Antenatal transmission of viral particles in neonates is rare, with suspicion of nosocomial infection in most cases. This abstract summarizes a case study of a neonate with MIS, presenting with cardiovascular, respiratory, and gastrointestinal involvement, along with fever and elevated biomarkers. Notable observations from similar cases include a predominance of cardiovascular and respiratory symptoms, albeit with variability in echo findings.

Multisystem Inflammatory Syndrome in Children: A Case Report.

This case report delves into the case of a patient in the Dominican Republic with multisystem inflammatory syndrome in children (MIS-C). MIS-C is a rare, hyper-inflammatory condition that develops in children as a delayed response to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, typically appearing with general markers of inflammation such as erythema and, in severe cases, cardiorespiratory symptoms. The three-year-old patient discussed in this report presented with signs of inflammation, such as erythema, rashes, and chapped skin, and reported experiencing diarrhea, vomiting, and fever for multiple days. Notably, a concurrent parasitic presence was found in the patient's fecal sample, and antibiotics were heavily used throughout the course of treatment. We explain the merits and drawbacks behind using antibiotic therapy for MIS-C and suggest steps that clinicians and researchers can take in order to minimize the potential misuse of antibiotics. Specifically, we identify that prioritizing tests for concurrent infections or illnesses is imperative in treating MIS-C patients, and we conclude by stating that using blood cultures and coprological examinations in tandem is an effective strategy for this purpose.

Proteomic Signatures of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Narrative Review.

BACKGROUND/OBJECTIVES: Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious complication of COVID-19. MIS-C has overlapping features with other pediatric inflammatory disorders including Kawasaki Disease (KD), Macrophage Activation Syndrome (MAS), Toxic Shock Syndrome and sepsis. The exact mechanisms responsible for the clinical overlap between MIS-C and these conditions remain unclear, and biomarkers that could distinguish MIS-C from its clinical mimics are lacking. This study aimed to provide an overview of how proteomic methods, like Mass Spectrometry (MS) and affinity-based proteomics, can offer a detailed understanding of pathophysiology and aid in the diagnosis and prognosis of MIS-C. METHODS: A narrative review of relevant studies published up to July 2024 was conducted. RESULTS: We identified 15 studies and summarized their key proteomic findings. These studies investigated the serum or plasma proteome of MIS-C patients using MS, Proximity Extension, or Aptamer-based assays. The studies associated the proteomic profile of MIS-C with laboratory and clinical parameters and/or compared it with that of other diseases including acute COVID-19, KD, MAS, pediatric rheumatic diseases, sepsis and myocarditis or pericarditis following COVID-19 mRNA immunization. Depending on the method and the control group, different proteins were increased or decreased in the MIS-C group. The limitations and challenges in MIS-C proteomic research are also discussed, and future research recommendations are provided. CONCLUSIONS: Although proteomics appear to be a promising approach for understanding the pathogenesis and uncovering candidate biomarkers in MIS-C, proteomic studies are still needed to recognize and validate biomarkers that could accurately discriminate MIS-C from its clinical mimics.

Complicated Pneumonia in a Child: Hydropneumothorax Associated with MIS-C and GAS Superinfection.

A hydropneumothorax is an uncommon complication of pneumonia, particularly in pediatric patients, and typically arises secondary to conditions such as malignancies, esophageal-pleural fistula, thoracic trauma, or thoracocentesis. While pneumothorax is rarely reported in adults with COVID-19 and is even less common in children, isolated cases have been noted in those with Multisystem Inflammatory Syndrome in Children (MIS-C). A recent alert has also been issued about increased Group A Streptococcus (GAS) infections in Europe. Against this background, the primary aim of this case report is to describe a rare and severe complication of pneumonia in a previously healthy child with MIS-C and a positive throat culture for GAS.

Surgical aspects of pediatric abdominal pain in the era of COVID-19: clinical consideration and outcomes.

Background: Acute abdominal pain in pediatrics is a medical emergency that requires special attention. During COVID-19 pandemic, this disease presented in pediatric age by different presentations including abdominal presentations.The affected children are presented with abdominal pain, which may be caused by surgical causes or by the virus itself that necessitate surgical consultation. Purpose: This study highlights the impact of the coronavirus pandemic on pediatric patients with acute abdominal pain regarding the presentation, clinical evaluation, and surgical management. Methods: A retrospective cohort study was done through the collection of data from medical records and authors' data repositories of pediatric patients presented with acute abdomen from March 2020 to March 2022, in three pediatric surgery tertiary centers. Results: Eighty-four pediatric patients with acute abdominal pain were included in this study. The diagnosis of acute appendicitis was found in 31 patients (36.9%). Generalized abdominal pain was noted in 17 patients (20.2%) and presentation mimicked acute cholecystitis was occured in 14 patients (16.7%). ultrasonography revealed intussusception in 12 cases (14.3%). Multisystem inflammatory syndrome in children (MIS-C) was present in 9 cases (10.7%) and only one case of pancreatitis (1.2%). Conservative management was successful in 66 cases (78.6%), while operative intervention was needed in18 cases (21.4%). Conclusion: During the COVID-19 pandemic, acute abdominal pain in children was frequently observed. Careful follow up is critically important as most cases do not necessitate surgical intervention. It is crucial to consider COVID-19 as a differential diagnosis in children presenting with acute abdominal pain, particularly in cases of atypical appendicitis and intussusception to prevent unnecessary surgical procedures.

Rare genetic variants of NLRP12 in Admixed Latino-American Children with SARS-CoV-2-related Multisystem Inflammatory Syndrome.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole-exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on NF-κB signaling. Nine rare, potentially deleterious variants were found in eight of 21 patients, located in IL17RC, IFNA10, or NLRP12 genes. Unlike the wild-type NLRP12 protein, which inhibits NF-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.

Asymptomatic SARS-COV2 Infection or COVID-19 vaccination effect for severe multisystem inflammatory syndrome in a 6-year-old girl: case report and review of the literature.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare complication, which develops within 3-6 weeks after SARS-CoV2 infection. The coronavirus disease 2019 (COVID-19) vaccine was firstly introduced in adults and adolescents and later in patients aged 5-11 years old. Although a reduced incidence of MIS-C and with less severe symptoms has been reported in vaccinated adolescents, there is little knowledge in children younger than 12 years of age. In addition, it is not understood whether MIS-C in vaccinated patients can be triggered by Covid19 vaccination or be secondary to a recent asymptomatic Sars-Cov2 infection. CASE PRESENTATION: We describe the case of a Caucasian 6-year-old girl, one month after double COVID-19 vaccination, who presented fever, acute abdominal pain, rash, pharyngotonsillitis, cheilitis, cervical lymphadenopathy without a prior detected Sars-Cov2 infection. She also had lymphopenia, increase in inflammatory markers, cardiac and pulmonary involvement. Therefore, we dosed both anti Sars-Cov2 Spike and Nucleocapsid antibodies, which were positive and allowed us to confirm the diagnosis of MIS-C. We promptly administered intravenous immunoglobulins and methylprednisone, resulting in the initial regression of fever. During the hospitalization, the child also developed pancreatitis and severe neurological involvement, including irritability, drowsiness, distal tremor, dyskinesia and buccal asymmetry with complete resolution after 2 months. After 3 months from the onset of the symptoms, she reported a transient loss of hair compatible with telogen effluvium. After 12 months of follow-up, she did not show any symptomatic sequelae. CONCLUSIONS: This case raises the question of whether COVID-19 vaccination may be involved in the pathogenesis of MIS-C in children between the ages of 5 and 11 years old.

Kawasaki Disease Diagnosis and Treatment in over 1000 Patients: A Continuum of Dysregulated Inflammatory Responses.

BACKGROUND: Kawasaki disease (KD) is a pediatric vasculitis, leading to coronary artery aneurysms (CAAs) in ~4-14%. Attention to the etiology and course of KD was generated by the close mimic of a SARS-CoV-2-induced phenotype, called multisystem inflammatory syndrome in children (MIS-C). METHODS: A total of 1179 cases were collected from 2012 with ~50% of cases retrospectively included. Clinical characteristics were described and risk factors for CAA (persistence) were investigated. Phenotypic patterns of the prospectively included KD patients were evaluated. These patterns were also compared to the seronegative KD and seropositive MIS-C cases identified during the SARS-CoV-2 pandemic. RESULTS: KD mostly affected boys and children < 5 years. IVIG resistance, CAAs, and giant CAAs occurred in 24.5%, 21.4%, and 6.6%, respectively. Giant CAAs were significantly more likely to normalize to a normal Z score in patients that were younger than 2.5 years old at the time of initial giant CAA (χ2 test p = 0.02). In our prospective (SARS-CoV-2-seronegative) KD series, there was a diminishing male predominance over time, whereas the proportions of incomplete presentations (p < 0.001) and patients with circulatory shock (p = 0.04) increased since the COVID-19 pandemic. Pre- and post-pandemic KD cases presented with different levels of C-reactive protein, thrombocyte counts, and hemoglobin levels over the years. Compared to pandemic KD, SARS-CoV-2-seropositive MIS-C patients were older (p < 0.001), and more often required intensive care admission (p < 0.001), with a gradual decrease over time between 2020 and 2022 (p = 0.04). KD carried a substantial risk of CAA development in contrast to MIS-C. CONCLUSION: the phenotypic changes seen over the last twelve years of our prospective follow-up study suggest a spectrum of hyperinflammatory states with potentially different triggering events within this clinical entity.

Clinical and Laboratory Parameters Associated with PICU Admission in Children with Multisystem Inflammatory Syndrome Associated with COVID-19 (MIS-C).

Background/Objectives: Multisystem Inflammatory Syndrome in children (MIS-C) is a rare but severe post-infectious complication of COVID-19 that often requires admission to the Pediatric Intensive Care Unit (PICU). The present study aimed to compare the demographic, clinical, and laboratory characteristics of children diagnosed with MIS-C who were admitted to the PICU and those who did not require PICU admission. Methods: Children diagnosed with MIS-C from September 2020 to April 2023 were included in this case-control study. Demographic, clinical, and laboratory data were collected from medical records. Results: Fifty children with MIS-C were included in the study [median (IQR) age: 7.5 (4.3, 11.4) years, 28/50 (56%) males]. Twenty-two (22/50, 44%) children required admission to the PICU. In the multivariate regression analysis, hepatic (OR: 12.89, 95%CI: 1.35-123.41, p-value = 0.03) and cardiological involvement (OR: 34.55, 95%CI: 2.2-541.91, p-value = 0.01) were significantly associated with hospitalization at the PICU. Regarding the laboratory and imaging parameters during the first 48 h from admission, D-dimer levels higher than 4 µg/mL and decreased Left Ventricular Ejection Fraction (LVEF) were associated with an increased risk of PICU admission (OR: 7.95, 95%CI: 1.48-42.78, p-value = 0.02 and OR = 1.28, 95%CI: 1.07-1.53, p-value = 0.01). Children who were admitted to the PICU were more likely to develop complications during their hospitalization (10/22, 45.5% vs. 3/28, 10.7%, p-value = 0.005) and were hospitalized for more days than children in the pediatric ward (median length of stay (IQR): 20 (15, 28) days vs. 8.5 (6, 14) days, p-value < 0.001). Conclusions: The findings of this study indicate that cardiovascular and hepatic involvement and increased D-dimer levels in children with MIS-C might be associated with admission to the PICU.

Long-term health outcome and quality of life in children with multisystem inflammatory syndrome: findings from multidisciplinary follow-up at an Italian tertiary-care paediatric hospital.

Multisystem inflammatory syndrome is a severe complication of SARS-CoV-2 infection in children (MIS-C). To date, data on long-term sequelae mainly concern cardiac outcomes. All ≤ 18 year olds consecutively admitted to the Buzzi Children's Hospital with a diagnosis of MIS-C between October 1, 2020, and May 31, 2022, were followed up for up to 12 months by a dedicated multidisciplinary team. They underwent laboratory tests, multi-organ clinical and instrumental assessments, and psychosocial evaluation. 56/62 patients, 40 M, mean age 8.7 years (95% CI 7.7, 9.7), completed the follow-up. Cardiological, gastroenterological, pneumological, and neurological evaluations, including IQ and EEG, were normal. Alterations of HOMA-IR index and/or TyG index, observed in almost all patients during hospitalisation, persisted in about a third of the population at 12 months. At 6 and 12 months respectively, impairment of adaptive functions was observed in 38/56 patients (67.9%) and 25/56 (44.6%), emotional and behavioural problems in 10/56 (17.9%) and 9/56 (16.1%), and decline in QoL in 14/56 (25.0%) and 9/56 (16.1%). Psychosocial well-being impairment was significantly more frequent in the subgroup with persistent glycometabolic dysfunction at 12 months (75% vs. 40.9% p < 0.001). CONLUSION: 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. Our study points 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. WHAT IS KNOWN: • Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. • Few data exist on the medium- and long-term outcomes of MIS-C, mostly focused on cardiac involvement. Emerging evidence shows neurological and psychological sequelae at mid- and long-term follow-up. WHAT IS NEW: • This study reveals that MIS-C may lead to long-term glycometabolic dysfunctions joined to impairment in the realm of general well-being and decline in quality of life, in a subgroup of children. • This study highlights the importance of a long-term multidisciplinary follow-up of children hospitalised with MIS-C, in order to detect the potential long-term sequelae in different areas of health, both physical and psychosocial well-being.