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During the pandemic of COVID-19, a novel atypical set of clinical findings was seen among several children with recent or current exposure to the virus. It was termed the multisystem inflammatory syndrome in children (MIS-C). Our study used the 2021 National Inpatient Sample to study the associations of sex, race, and age with the incidence of MIS-C among COVID-19-positive children. Out of 69,440 COVID-19-positive children, 2,790 (4.0%) reported MIS-C. The incidence of MIS-C was highest among those aged 8 years old (17,130 MIS-C cases per 100,000 COVID-19 patients), Asian or Pacific Islanders (API) (5,346 MIS-C per 100,000 COVID-19 cases), and males (4,734 cases per 100,000 COVID-19 cases). Furthermore, 7.9% of MIS-C cases met the classification of Kawasaki disease.

Multisystem inflammatory syndrome of children (MIS-C) is a clinical picture that entered the medical nomenclature after the coronavirus disease 2019 pandemic. Although it primarily affects older children, there have been a limited number of cases reported during the neonatal period. Herein we present a patient, a late preterm infant, with severe MIS-C-related cerebral sinus venous thrombosis who was successfully treated with therapeutic plasma exchange. Practitioners can consider therapeutic plasma exchange as a safe and effective option for the treatment of critically ill MIS-C cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study aimed to identify clinical characteristics to differentiate multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) in Taiwan, an island with a delayed cluster of MIS-C and a high incidence of KD. Additionally, we studied risk factors for developing severe complications in patients with MIS-C. We conducted a retrospective, multicenter, cohort, and observational study that linked data on patients with MIS-C between May and December 2022 and patients with KD between 2019 and 2021 from 12 medical centers. Hemodynamic compromise, defined as the need for inotropic support or fluid challenge, was recorded in patients with MIS-C. We also evaluated maximal coronary Z-scores before treatment and one month after disease onset. A total of 83 patients with MIS-C and 466 patients with KD were recruited. A 1:1 age and gender-matched comparison of 68 MIS-C and KD pairs showed that MIS-C patients had a lower percentage of positive BCG red halos, lower leukocyte/platelet counts, more gastrointestinal symptoms, and a higher risk of hemodynamic compromise. In Taiwan, 38.6% of MIS-C patients experienced hemodynamic compromise, with presence of conjunctivitis and elevated levels of procalcitonin (>1.62 ng/mL) identified as independent risk factors. We identified two independent risk factors associated with hemodynamic compromise in MIS-C patients. The comparison between matched MIS-C and KD patients highlighted significant differences in clinical presentations, like BCG red halos, which may aid in the differential diagnosis of the two disease entities, especially in regions with a high incidence rate of KD. [ABSTRACT FROM AUTHOR]

Background: COVID-19 has significant effects on organ function, particularly on lung function and iron metabolism. Studies have shown increased levels of ferritin, an iron storage protein, in COVID-19 patients, indicating potential changes in iron utilization. Research has focused primarily on adults, with limited studies on paediatric patients and a lack of comparisons with MIS-C patients. This study aimed to assess iron status in paediatric COVID-19 patients using traditional and new biomarkers, soluble transferrin receptors (sTfR) and Reticulocyte hemoglobin equivalent (RET-He), to improve diagnosis and prognosis. Additionally, we sought to compare iron status between acute COVID-19 patients and MIS-C patients and evaluate the relationships among iron dysmetabolism, disease severity, and prognosis in paediatric patients. The study also involved monitoring iron status during and after infection to understand its impact on patient severity and prognosis. Methods: A cohort study involving 49 patients aged 1 month to 18 years was conducted at the isolation department of Mansoura University Children's Hospital. The study included 36 patients with acute COVID-19 and 13 with multisystem inflammatory syndrome of childhood (MIS-C). Diagnosis was based on PCR from a deep nasopharyngeal swab or a positive antibody test. Follow-up of survivors was conducted 3 months after recovery. Blood samples were obtained during infection and at follow-up for CBC, Ret-He, iron kinetics, and sTfR analyses. Results: Significant iron deficiency anaemia was observed in all patients during infection, with improvement after 3 months of recovery in survivors. The improvement was more obvious in MIS-C patients, with Hb and iron kinetics not significantly affected by disease severity. The STfR was significantly lower in nonsurvivors than in survivors. The ROC curve showed that a baseline sTfR ≤ 18 nmol/L was a statistically significant difference between nonsurvivors and survivors (area under the curve (AUC) = 0.810, p <.001), with 66.7% sensitivity and 82.5% specificity. Regression analysis revealed that patients with baseline sTfRs ≤ 18 nmol/L were 5.9 times more susceptible to death. Conclusion: This study revealed that COVID-19 in children caused iron deficiency anaemia, which improved within 3 months after recovery. Haemoglobin and sTfRs were identified as reliable indicators of IDA in these patients, unlike iron kinetics and RET-He. [ABSTRACT FROM AUTHOR]

Objective: Multisystem inflammatory syndrome in children (MIS-C) is a critical childhood disease that is associated with coronavirus disease (COVID-19). We aimed to describe the clinical, laboratory, and echocardiographic characteristics and outcome of critical MIS-C cases in Egyptian children during the first wave of the COVID-19 pandemic. Design: A retrospective, observational study. Setting: A single-center tertiary pediatric intensive care unit (PICU).In Ain Shams university hospitals Cairo Egypt Methods: Children admitted to the PICU diagnosed with severe MIS-C as per the Centers for Disease Control's definition from June 23, 2020, to August 22, 2020, were included. Results: The patient's mean age was 7.45 (interquartile range [IQR], 4.23) years, and the cause of PICU admission was hypotension and shock. All patients had a fever for 4.8 (IQR, 2.5) days before shock developed. Overall, 68% had a gastrointestinal manifestation, and 55.6% had a rash. Thirty-five of 45 patients had ≥ 4 elevated inflammatory markers. The cardiac troponin I level was elevated in 35 of 45 patients. The most common cardiac condition was valvulitis (tricuspid regurgitation, 29/45; mitral valve regurgitation, 28/45; pulmonary valve regurgitation, 5/45; atrial valve regurgitation, 4/45). Twenty-one patients had an impaired ejection fraction < 50%, and 17 patients had coronary dilatation. Six patients had pericardial effusion, 1 patient had dilated pulmonary arteries, and 6 patients (13.3%) died of their associated comorbidities. The mean PICU length of stay among patients with no associated comorbidities was 7 days. Conclusions: Critical cases of MIS-C had a spectrum of different cardiac conditions, with valvulitis being the most common one. The worst outcome occurred in patients with comorbidities and infants. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) complications are significant manifestations of COVID-19 and are increasingly being recognized. These complications range from severe acute pancreatitis to colitis, adding complexity to diagnosis and management. A comprehensive database search was conducted using several databases. Our inclusion criteria encompassed studies reporting severe and long-term GI complications of COVID-19. Digestive disorders were categorized into infections, inflammatory conditions, vascular disorders, structural abnormalities, other diagnoses, and undiagnosed conditions. Of the 73 studies that were selected for full-text review, only 24 met our inclusion criteria. The study highlights a broad range of gastrointestinal complications following COVID-19 infection (excluding liver complications, which are examined separately), including inflammatory conditions, such as ulcerative colitis (UC), acute pancreatitis, and multisystem inflammatory syndrome in children (MIS-C). Other GI complications were reported such as vascular disorders, including diverse thrombotic events and structural abnormalities, which ranged from bowel perforations to adhesions. Additionally, undiagnosed conditions like nausea and abdominal pain were prevalent across different studies involving 561 patients. The findings emphasize the substantial impact of COVID-19 on the GI tract. Ongoing research and monitoring are crucial to understanding the long-term effects and developing effective management strategies for these complications. [ABSTRACT FROM AUTHOR]

Objective: Delirium is an under-recognized problem in critically ill children. Although delirium is common in adults hospitalized with COVID-19, the relationship between pediatric COVID-19 and delirium has not been described. To address this gap, we characterized delirium in critically ill children with different manifestations of COVID-19 and investigated associations among demographic, disease, and treatment factors. We hypothesized that multisystem inflammatory syndrome in children (MIS-C) would be associated with a higher incidence of delirium given its underlying pathophysiology of hyperinflammation. Design: Retrospective, single-center cohort study. Setting: Quaternary-care pediatric intensive care unit (PICU). Patients: Children less than 18 years of age hospitalized in the PICU between March 2020 and March 2023 with either active SARS-CoV-2 infection or serological evidence of prior infection. Measurements and main results: The cohort included 149 PICU hospitalizations among children with evidence of COVID-19. Patients were categorized by reason for PICU admission: 75 (50%) for COVID-19 respiratory disease, 36 (24%) MIS-C, and 38 (26%) any other primary reason with positive COVID-19 testing. Delirium was diagnosed in 43 (29%) patients. Delirium incidence was highest in patients requiring invasive mechanical ventilation (IMV) (56% vs 7.5% in patients who did not require IMV, p <.001). Patients who were exposed to opioids, dexmedetomidine, paralytics or benzodiazepines more frequently experienced delirium compared to those unexposed (p <.001, p <.001, p <.001 and p =.001, respectively). After multivariable adjustment, delirium was associated with IMV (HR 3 [95% CI 1.5–5.7]), female sex (HR 2.4 [1.2–4.7]), and developmental disability (HR 3.4 [95% CI 1–11.1]). There was no association between delirium and reason for PICU hospitalization. Conclusions: Delirium was common among children hospitalized with COVID-19. The overall incidence was much less than has been reported in adults with COVID-19. Delirium reduction efforts should focus on children with developmental disability and minimizing ongoing risks during IMV. [ABSTRACT FROM AUTHOR]

Background: Multiple reports have described myopericarditis following mRNA COVID-19 vaccination. However, data on the persistence of subclinical myocardial injury assessed by left ventricular (LV) longitudinal strain (LVLS) is limited. Objectives: Our aim was to assess LV function longitudinally in our cohort of COVID-19 vaccine-related myopericarditis using ejection fraction (EF), fractional shortening (FS), LVLS, and diastolic parameters. Methods: Retrospective, single-center review of demographic, laboratory, and management data was performed on 20 patients meeting diagnostic criteria for myopericarditis after mRNA COVID-19 vaccination. Echocardiographic images were obtained on initial presentation (time 0), at a median of 12 days (7.5, 18.5; time 1), and at a median of 44 days (29.5, 83.5; time 2). FS was calculated by M-mode, EF by 5/6 area-length methods, LVLS by utilization of TOMTEC software, and diastolic function by tissue Doppler. All parameters were compared across pairs of these time points using Wilcoxon signed-rank test. Results: Our cohort consisted predominantly of adolescent males (85%) with mild presentation of myopericarditis. The median EF was 61.6% (54.6, 68.0), 63.8% (60.7, 68.3), 61.4% (60.1, 64.6) at times 0, 1, and 2, respectively. Upon initial presentation, 47% of our cohort had LVLS < -18%. The median LVLS was -18.6% (-16.9, -21.0) at time 0, -21.2% at time 1 (-19.4, -23.5) (p = 0.004) and -20.8% (-18.7, -21.7) at time 2 (p = 0.004, as compared to time 0). Conclusions: Though many of our patients had abnormal strain during acute illness, LVLS improved longitudinally, indicating myocardial recovery. LVLS can be used as marker of subclinical myocardial injury and risk stratification in this population. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to compare and contrast Kawasaki disease (KD) with multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic. Methods: A retrospective analysis of the medical records of patients diagnosed with KD and MIS-C at a single institution from July 2020 to November 2021 was performed. Results: The study included 39 MIS-C patients (84.6% male) with a median age of 138 months and 17 KD patients (58.8% male) with a median age of 36 months. The MIS-C patients were older (p < 0.001) and had prolonged hospitalizations (p = 0.023), elevated neutrophil counts (p < 0.001), C-reactive protein (p < 0.001), procalcitonin (p < 0.001), interleukin-6 (p < 0.014), ferritin (p < 0.001), fibrinogen (p < 0.001), troponin I (p = 0.001), NT-proBNP (p < 0.001), and D-dimer levels (p < 0.001). There were more cases of hypotension (p = 0.024), decreased left ventricular function (p = 0.023), and a greater need for corticosteroids (p < 0.001), enoxaparin (p = 0.045), and therapeutic plasma exchange (p < 0.001). Kawasaki disease patients had a greater incidence of rash (p < 0.001), changes in oral mucosa (p < 0.001), conjunctival injection (p < 0.001), extremity changes (p < 0.001), and cervical lymphadenopathy (p < 0.001). They had a longer duration of fever (p < 0.001), elevated white blood cell count (p < 0.001), platelet count (p < 0.001), and alanine aminotransferase level (p < 0.001). The two groups were similar regarding the hemoglobin levels, erythrocyte sedimentation rates, albumin levels, and the frequency of coronary aneurysm, myocarditis, pericarditis, invasive mechanical ventilatory support, and intravenous immunoglobulin treatment. Conclusions: Advanced patient age, a greater presence of gastrointestinal and cardiac findings associated with hypotension, increased NT-proBNP levels, decreased left ventricular function, the use of various treatment modalities, and longer hospital stays suggest MIS-C, whereas prolonged fever and classical clinical features of KD favor KD. [ABSTRACT FROM AUTHOR]

Background: Multisystem inflammatory syndrome in children (MIS-C) is one of the complications of SARS-CoV-2 infection. This study aims to evaluate the clinical and laboratory characteristics, as well as treatment results, of MIS-C patients who received intravenous immunoglobulin (IVIG) monotherapy. Methods: This retrospective study included patients diagnosed with MIS-C. Demographic data, organ involvements at the admission, laboratory evaluations for diagnosis, treatment, and follow-up were recorded. We evaluated outcomes by the length of the intensive care unit stay, the total hospitalization period, complications, and mortality. Results: A total of 95 patients diagnosed with MIS-C were evaluated. The mean age was 118.8 (± 52.5) months. 76.8% of the patients had four or more organ systems involved. Seventy-nine patients (83%) were hospitalized in the pediatric intensive care unit (PICU) for a mean of 4.59 days. Seventy-seven (81%) patients received IVIG. A second dose of IVIG was administered to 66.3% of patients. All patients received vitamin D and C supplementation. Six patients who had cardiac involvement or cerebral infarction were treated with plasmapheresis. No patients received steroids. There was no mortality at the end of the follow-up. Conclusions: Favorable outcomes may be obtained with IVIG monotherapy in MIS-C patients. More clinical trials are needed to establish the role of supportive treatments like vitamin D and C in MIS-C management. [ABSTRACT FROM AUTHOR]

Inflammatory syndromes, including those caused by infection, are a major cause of hospital admissions among children and are often misdiagnosed because of a lack of advanced molecular diagnostic tools. In this study, we explored the utility of circulating cell-free RNA (cfRNA) in plasma as an analyte for the differential diagnosis and characterization of pediatric inflammatory syndromes. We profiled cfRNA in 370 plasma samples from pediatric patients with a range of inflammatory conditions, including Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), viral infections, and bacterial infections. We developed machine learning models based on these cfRNA profiles, which effectively differentiated KD from MIS-C--two conditions presenting with overlapping symptoms--with high performance [test area under the curve = 0.98]. We further extended this methodology into a multiclass machine learning framework that achieved 80% accuracy in distinguishing among KD, MIS-C, viral, and bacterial infections. We further demonstrated that cfRNA profiles can be used to quantify injury to specific tissues and organs, including the liver, heart, endothelium, nervous system, and the upper respiratory tract. Overall, this study identified cfRNA as a versatile analyte for the differential diagnosis and characterization of a wide range of pediatric inflammatory syndromes. [ABSTRACT FROM AUTHOR]

A severe consequence of SARS-CoV-2 infection that manifests as systemic inflammation and multi-organ involvement is called Multisystem Inflammatory Syndrome in Children (MIS-C). This review examines the possible relationship between gut barrier integrity, the microbiome, dysregulation of interleukin 6 (IL-6) signaling, and MIS-C. Clinical and biochemical features of MIS-C are comparable to those of other hyper-inflammatory syndromes, suggesting a dysregulated immune response. One possible explanation for the systemic inflammation seen in MIS-C patients is the SARS-CoV-2-induced dysregulation of the IL-6 signaling pathway. In addition, new data suggest a reciprocal link between gut barrier integrity and IL-6. SARS-CoV-2 exhibits bacteriophage-like behavior, highlighting the role of bacteria as a reservoir for the virus and emphasizing the importance of understanding the bacteriophagic mechanism of the virus in fecal–oral transmission. The increased translocation of viral products and bacterial toxins may result from disrupting the intestinal barrier and cause systemic inflammation. On the other hand, systemic inflammation can weaken the integrity of the intestinal barrier, which feeds back into the loop of immunological dysregulation. In the context of MIS-C, understanding the interaction between SARS-CoV-2 infection, IL-6, and gut barrier integrity may shed light on the etiology of the disease and guide treatment options. Since children with gut dysbiosis may be more susceptible to MIS-C, it is critical to reinforce their microbiome through probiotics supplementation, and plant-fiber-rich diets (prebiotics). Early antibiotic treatment and the use of zonulin antagonists should also be considered. [ABSTRACT FROM AUTHOR]

Background: Multisystem inflammatory syndrome in children (MIS-C) occurs after SARS-CoV-2 infection, with gastrointestinal symptoms a prominent feature. This syndrome has been proposed to be triggered by persistent SARS-CoV-2 antigenemia due to increased intestinal epithelial permeability. We obtained evidence for this in this study. Methods: In a single-centre study, we recruited 83 children and analysed blood samples to quantify the circulating markers of increased intestinal permeability following SARS-CoV-2 infection. Publicly available proteomics MIS-C datasets were also accessed to assess the evidence for increased intestinal permeability. We further quantified SARS-CoV-2 antigenemia and the humoral response to SARS-CoV-2 spike protein. Results: Following SARS-CoV-2 infection, healthy children demonstrated no dysregulation of the intestinal epithelial barrier. In MIS-C, considerable increases in markers of epithelial dysfunction were observed, with similar increases noted in febrile controls. Furthermore, we found little evidence of persistent SARS-CoV-2 antigenemia in MIS-C. Conclusions: Our results suggest that although increased intestinal epithelial permeability is a feature of MIS-C, it is not unique to the condition, and persistent SARS-CoV-2 antigenemia does not occur. [ABSTRACT FROM AUTHOR]

Background: This study was conducted to ascertain the most frequent symptoms of COVID-19 infection at first consultation in a pediatric cohort and to devise a predictive model for hospitalization. Methods: This is a retrospective cross-sectional study of 1028 Brazilian patients aged <18 years with SARS-CoV-2 infection in a single reference hospital in the first year of the pandemic. Clinical, demographic, laboratory, and disease spectrum data were analyzed via multivariate logistic regression modeling to develop a predictive model of factors linked to hospitalization. Results: The majority of our cohort were schoolchildren and adolescents, with a homogeneous distribution concerning sex. At first consultation, most patients presented with fever (64.1%) and respiratory symptoms (63.3%). We had 204 admitted patients, including 11 with Pediatric Multisystem Inflammatory Syndrome. Increased D-dimer levels were associated with comorbidities (p = 0.018). A high viral load was observed in patients within the first two days of symptoms (p < 0.0001). Our predictive model included respiratory distress, number and type of specific comorbidities, tachycardia, seizures, and vomiting as factors for hospitalization. Conclusions: Most patients presented with mild conditions with outpatient treatment. However, understanding predictors for hospitalization can contribute to medical decisions at the first patient visit. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article discusses a case of a 13-year-old boy who developed Febrile Infection-Related Epilepsy Syndrome (FIRES) after contracting COVID-19. FIRES is a subtype of New-Onset Refractory Status Epilepticus (NORSE) characterized by new-onset status epilepticus without a clear cause. The boy was treated with Anakinra, a medication used for rheumatologic conditions, and showed a rapid response with seizure control. The article highlights the potential use of Anakinra in COVID-19-associated FIRES and the importance of early treatment. It also mentions the presence of the "claustrum sign" on imaging, which is a biomarker for FIRES. [Extracted from the article]

Aim: To comprehensively review the literature on multisystem inflammatory syndrome in children (MIS‐C). Methods: Narrative review of relevant studies published between April 2020 and January 2024. Results: MIS‐C is a SARS‐CoV‐2‐related hyperinflammatory syndrome developing 2–6 weeks after COVID‐19 in genetically susceptible individuals. Persisting fever, mucocutaneous manifestations, GI and cardiac involvement, together with lymphopenia and elevated inflammatory and cardiac markers are the main clinical features. It is believed to recognise some pathogenetic and clinical overlap with Kawasaki disease. New case definitions have been proposed after an assessment of the diagnostic performance of existing criteria; epidemiological criterion is however progressively losing its usefulness as the pandemic turns into an endemic and in the areas with the highest rates of COVID‐19 vaccination. Current guidelines recommend both intravenous immunoglobulin and glucocorticoids in the first‐line immunomodulatory treatment, mainly based on comparative retrospective cohorts; the actual role of biologics remains to be adequately established. Strict follow‐up is mandatory, especially for those with severe cardiac involvement, as longitudinal studies evaluate the long‐term evolution of cardiac damage. Conclusion: In this paper, we review the epidemiological, pathogenetic, clinical and prognostic features of MIS‐C, and outline the main questions which still remain unanswered after more than 3 years of research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Objective: To evaluate long-term posterior segment findings in children recovering from multisystemic inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. Patients and Methods: Our study included 22 patients who were admitted to an intensive care unit with a diagnosis of MIS-C between November 2021 and March 2022, and 25 healthy controls. The study included pediatric patients who had an eye examination an average of 12.35 ± 2.18 months after recovery from MIS-C. Detailed eye examinations and measurements of all participants were obtained retrospectively from patient files. Posterior segment parameters were measured using swept-source optical coherence tomography (OCT) and OCT-angiography (OCT-A); these parameters included peripapillary retinal nerve fiber layer (pRNFL) thickness, central macular thickness (CMT), subfoveal choroidal thickness (SCT), macular vascular densities (VD), and foveal avascular zone (FAZ) area. Results: Mean age was 9.7 ± 3.6 years in the MIS-C group and 10.6 ± 2.8 years in the healthy control group (P = 0.316). There were no statistically significant differences between the MIS-C group and the healthy control group in terms of pRNFL thickness, CMT, and SCT. However, in the MIS-C group, the macular superficial vascular plexus and deep vascular plexus showed significantly lower VD in the superior, inferior, nasal, and temporal quadrants compared to the healthy controls (P < 0.05 for all). A comparison of the superficial and deep FAZ area parameters of both groups showed no statistically significant difference (P > 0.05). Conclusions: We showed that patients who had recovered from MIS-C had retinal vascular damage at the long-term follow-up. Following up with these patients after recovery with OCT and OCT-A, which are noninvasive methods commonly used in the detailed evaluation of the posterior segment of the eye, could be beneficial for understanding the long-term effects of MIS-C on retinal microvasculature. [Ophthalmic Surg Lasers Imaging Retina 2024;55:518–526.] [ABSTRACT FROM AUTHOR]

Background. Due to the rarity of the combination of emergence diabetes mellitus type 1 (DM1), COVID-19, and multisystem inflammatory syndrome, each reported case represents valuable experience and increases the awareness of medical professionals. Clinical case description. A 7-year-old boy was admitted to the intensive care unit with a diagnosis of diabetes mellitus type 1, first identified. On day 2, ketoacidotic coma with a hyperosmolar component developed, a positive polymerase chain reaction (PCR) test for SARS-CoV-2 was obtained, and a picture of subarachnoid hemorrhage was described according to CT scans of the brain. On day 3, macrohematuria, peripheral edema, pasty complexion were noted; the clinical picture and laboratory examination data corresponded to a “cytokine storm” with the development of multiple organ failure. On day 5, tonic-clonic seizures and bloody discharge from the nasopharynx were noted. On day 6, a negative PCR test for SARS-CoV-2 was obtained, on chest X-rays there was a heterogeneous decrease in pneumatization in the basal sections on both sides, and bilateral hydrothorax. On day 9, meningeal symptoms were noted. On day 14, a repeated episode of a convulsive attack was registered, and changes in the brain according to MRI results were regarded as an inflammatory demyelinating lesion against the background of the course of multisystem inflammatory syndrome and DM or as posterior reversible encephalopathy (PRES syndrome). Against the background of the appointment of immunomodulatory, anticoagulant, antibacterial, antiviral therapy, positive dynamics was noted in the child's condition. On day 18, the patient in a stable condition of moderate severity was transferred to the Department of Pediatric Endocrinology for further treatment. After 14 days, the child was discharged from the hospital in a satisfactory condition. Conclusion. This case report may confirm the risk of developing multisystem inflammatory syndrome in children with DM1 and COVID-19, which requires an interdisciplinary approach and the appointment of therapy included in the standards of management of children with multisystem inflammatory syndrome.

Studies on the severity in multisystem inflammatory syndrome in children (MIS-C) show heterogeneous results and may not reflect a global perspective. This systematic review aims to estimate the frequency of in-hospital unfavorable outcomes in patients with MIS-C over the 3 years since the onset of the SARS-CoV-2 pandemic. A systematic search was conducted in Medline, Scopus, Embase, Cochrane, Web of Science, Scielo, and preprint repositories until December 15, 2022. Study selection and data extraction were evaluated independently. The primary outcomes were intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and death. Additionally, we evaluated cardiovascular-related outcomes. We performed a random-effects model meta-analysis and assessed the certainty of the evidence. Fifty-seven studies (n = 13 254) were included. The frequency of ICU admission was 44.7% (95% CI 38.8–50.7), 11.9% for IMV (95% CI 9.6–14.4), and 2.0% for death (95% CI 1.3–3.0). The requirement of vasoactive/inotropic drugs was 40.1% (95% CI 35.9–44.4), 7.9% for coronary aneurysm (95% CI 4.1–12.7), 30.7% for decreased left ventricle ejection fraction (LVEF) (95% CI 26.3–35.4), and 29.7% for myocarditis (95% CI 18.4–42.4). We assess the included evidence as being of very low certainty. Finally, excess COVID-19 mortality by country and the diagnostic criteria for MIS-C (CDC compared to WHO) were associated with a higher frequency of ICU admissions. The year of study conduction (2022 compared to 2020) was associated with a lower frequency of IMV. Conclusion: The frequency of in-hospital unfavorable outcomes in patients with MIS-C was high. Well-designed studies are needed to explore other heterogeneity sources. Protocol registration: CRD42021284878. What is Known: • Multisystem inflammatory syndrome in children (MIS-C) is a serious post-infectious condition linked to SARS-CoV-2. Studies on the severity of MIS-C show heterogeneous results. These findings may not be representative of the reality in other regions, making it challenging to draw generalizable conclusions. What is New: • Over the 3 years since the onset of the SARS-CoV-2 pandemic, our systematic review has shown that the frequency of in-hospital unfavorable outcomes in patients with MIS-C is high, with a very low certainty of the evidence. Our results reflect the reality from a global perspective, across different countries with varying income levels. • The main sources of heterogeneity in the frequency of severe outcomes could be explained by the excess mortality due to COVID-19 in each country, the type of diagnostic criteria for MIS-C, and the year the study was conducted. [ABSTRACT FROM AUTHOR]

Introduction: Our study aims to investigate the association between cardiac involvement in multisystem inflammatory syndrome in children (MIS-C) and the patient’s epidemiological, clinical, and investigative profile. Identifying such associations could facilitate the early detection and management of cardiac complications, potentially leading to improved patient outcomes. Materials and Methods: The study was conducted as a prospective observational study at SAT Hospital, Government Medical College, Thiruvananthapuram. It included all children aged 0–12 years admitted during the study period who met the criteria for the diagnosis of MIS-C as per the guidelines provided by the World Health Organization. Exclusion criteria comprised children with a confirmed alternative diagnosis, preexisting heart disease, and those whose parents declined consent for participation. Despite aiming for a sample size of 55 based on previous studies, only 50 samples were obtained within the study period. Ethical considerations were met and no funding was involved in our study. A well-structured pro forma was used for data collection. Results: Our study included 50 children aged under 12 years, with a median age of 7 years, and an interquartile range of 4.6 years. Of these participants, 54% were male, and the remaining 46% were female. According to the operational definition utilized in our study, 62% of the children exhibited cardiac involvement, while 38% had a normal cardiac status. In our investigation, the median values for C-reactive protein and erythrocyte sedimentation rate were found to be 10 mg/dl and 60 mm/h, respectively. Furthermore, the median platelet count was observed to be 1.87 lakhs/mm3, while the median absolute lymphocyte count was recorded as 1472 cells/mm3. Serum albumin and NT-pro BNP were identified to have a statistically significant association with cardiac involvement, exhibiting significance at the 1% level. Conclusion: Our findings suggest that serum albumin and NT-pro BNP have a statistically significant association with cardiac involvement in MIS-C. Furthermore, hemodynamic instability in MIS-C may result primarily from vasculopathy rather than cardiac dysfunction.

Abstract Background Multisystem Inflammatory Syndrome in Children (MIS-C) associated with SARS-CoV-2 can lead to severe cardiovascular complications. Anakinra, an interleukin-1 receptor antagonist, is proposed to benefit the hyperinflammatory state of MIS-C, potentially improving cardiac function. This systematic review evaluated the effectiveness of early Anakinra administration on cardiac outcomes in children with MIS-C. Methods A comprehensive search across PubMed, Embase, and Web of Science until March 2024 identified studies using Anakinra to treat MIS-C with reported cardiac outcomes. Observational cohorts and clinical trials were included, with data extraction focusing on cardiac function metrics and inflammatory markers. Study quality was assessed using the Newcastle-Ottawa Scale. Results Six studies met the inclusion criteria, ranging from retrospective cohorts to prospective clinical studies, predominantly from the USA. Anakinra dosages ranged from 2.3 to 10 mg/kg based on disease severity. Several studies showed significant improvements in left ventricular ejection fraction and reductions in inflammatory markers like C-reactive protein, suggesting Anakinra’s role in enhancing cardiac function and mitigating inflammation. However, findings on vasoactive support needs were mixed, and some studies did not report significant changes in acute cardiac support requirements. Conclusion Early Anakinra administration shows potential for improving cardiac function and reducing inflammation in children with MIS-C, particularly those with severe manifestations. However, the existing evidence is limited by the observational nature of most studies and lacks randomized controlled trials (RCTs). Further high-quality RCTs are necessary to conclusively determine Anakinra’s effectiveness and optimize its use in MIS-C management for better long-term cardiac outcomes and standardized treatment protocols.

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with SARS-CoV-2 can lead to severe cardiovascular complications. Anakinra, an interleukin-1 receptor antagonist, is proposed to benefit the hyperinflammatory state of MIS-C, potentially improving cardiac function. This systematic review evaluated the effectiveness of early Anakinra administration on cardiac outcomes in children with MIS-C. Methods: A comprehensive search across PubMed, Embase, and Web of Science until March 2024 identified studies using Anakinra to treat MIS-C with reported cardiac outcomes. Observational cohorts and clinical trials were included, with data extraction focusing on cardiac function metrics and inflammatory markers. Study quality was assessed using the Newcastle-Ottawa Scale. Results: Six studies met the inclusion criteria, ranging from retrospective cohorts to prospective clinical studies, predominantly from the USA. Anakinra dosages ranged from 2.3 to 10 mg/kg based on disease severity. Several studies showed significant improvements in left ventricular ejection fraction and reductions in inflammatory markers like C-reactive protein, suggesting Anakinra's role in enhancing cardiac function and mitigating inflammation. However, findings on vasoactive support needs were mixed, and some studies did not report significant changes in acute cardiac support requirements. Conclusion: Early Anakinra administration shows potential for improving cardiac function and reducing inflammation in children with MIS-C, particularly those with severe manifestations. However, the existing evidence is limited by the observational nature of most studies and lacks randomized controlled trials (RCTs). Further high-quality RCTs are necessary to conclusively determine Anakinra's effectiveness and optimize its use in MIS-C management for better long-term cardiac outcomes and standardized treatment protocols. [ABSTRACT FROM AUTHOR]

Background Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent infection with severe acute respiratory syndrome coronavirus 2, but the underlying immunological mechanisms driving this distinct syndrome are unknown. Methods We utilized high-dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute coronavirus disease 2019 (SAC). Results Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen-presenting cells. Interleukin 27 (IL-27), a cytokine known to drive hematopoietic stem cells toward EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood. Conclusions Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing toward MIS-C, offering potential diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Coagulation disorders are common in Kawasaki disease (KD). The main objectives of the present study were to probe the associations of coagulation profiles with clinical classification, IVIG responsiveness, coronary artery abnormalities (CAAs) in the acute episode of KD. A total of 313 KD children were recruited and divided into six subgroups, including complete KD (n = 217), incomplete KD (n = 96), IVIG-responsive KD (n = 293), IVIG-nonresponsive KD (n = 20), coronary artery noninvolvement KD (n = 284) and coronary artery involvement KD (n = 29). Blood samples were collected within 24-h pre-IVIG therapy and 48-h post-IVIG therapy. Coagulation profiles, conventional inflammatory mediators and blood cell counts were detected. Echocardiography was performed during the period from 2- to 14-day post-IVIG infusion. In addition, 315 sex- and age-matched healthy children were enrolled as the controls. (1) Before IVIG therapy, coagulation disorders were more prone to appear in KD patients than in healthy controls, and could be overcome by IVIG therapy. FIB and DD significantly increased in the acute phase of KD, whereas reduced to normal levels after IVIG therapy. (2) PT and APTT were significantly longer in patients with complete KD when compared with their incomplete counterparts after IVIG therapy. (3) The larger δDD, δFDP and the smaller δPT, δINR predicted IVIG nonresponsiveness. (4) The higher δDD and δFDP correlated with a higher risk for CAAs (DD: r = −0.72, FDP: r = −0.54). Coagulation disorders are correlated with complete phenotype, IVIG nonresponsiveness and CAA occurrence in the acute episode of KD, and can be rectified by synergistic effects of IVIG and aspirin. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to a diverse pattern of myocardial injuries, including myocarditis, which is linked to adverse outcomes in patients. Research indicates that myocardial injury is associated with higher mortality in hospitalized severe COVID-19 patients (75.8% vs 9.7%). Cardiovascular Magnetic Resonance (CMR) has emerged as a crucial tool in diagnosing both ischaemic and non-ischaemic myocardial injuries, providing detailed insights into the impact of COVID-19 on myocardial tissue and function. This review synthesizes existing studies on the histopathological findings and CMR imaging patterns of myocardial injuries in COVID-19 patients. CMR imaging has revealed a complex pattern of cardiac damage in these patients, including myocardial inflammation, oedema, fibrosis, and ischaemic injury, due to coronary microthrombi. This review also highlights the role of LLC criteria in diagnosis of COVID-related myocarditis and the importance of CMR in detecting cardiac complications of COVID-19 in specific groups, such as children, manifesting multisystem inflammatory syndrome in children (MIS-C) and athletes, as well as myocardial injuries post-COVID-19 infection or following COVID-19 vaccination. By summarizing existing studies on CMR in COVID-19 patients and highlighting ongoing research, this review contributes to a deeper understanding of the cardiac impacts of COVID-19. It emphasizes the effectiveness of CMR in assessing a broad spectrum of myocardial injuries, thereby enhancing the management and prognosis of patients with COVID-19 related cardiac complications. [ABSTRACT FROM AUTHOR]

First described in 2020, multi-system inflammatory syndrome in children (MIS-C) is an, initially life-threatening, disease characterised by severe inflammation and following exposure to SARS-CoV-2. The immunopathology of MIS-C involves a hyperinflammation characterised by a cytokine storm and activation of both the innate and adaptive immune system, eventually leading to multi-organ failure. Several etiological theories are described in literature. Firstly, it is suggested that the gut plays an important role in the translocation of microbial products to the systemic circulation. Additionally, the production of autoantibodies that develop after the initial infection with SARS-CoV-2 might lead to many of its broad clinical symptoms. Finally, the superantigen theory where non-specific binding of the SARS-CoV-2 spike glycoprotein to the T-cell receptor leads to a subsequent activation of T cells, generating a powerful immune response. Despite the sudden outbreak of MIS-C and alarming messages, as of 2024, cases have declined drastically and subsequently show a less severe clinical spectrum. However, subacute cases not meeting current diagnostic criteria might be overlooked even though they represent a valuable research population. In the future, research should focus on adjusting these criteria to better understand the broad pathophysiology of MIS-C, aiding early detection, therapy, and prediction. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is frequently associated with thrombo inflammation, which can predispose to developing of life-threatening conditions in children such as the multisystem inflammatory syndrome (MIS-C) and Kawasaki disease. Because of the consistent overlap in pathogenesis and symptoms, identifying laboratory tests that may aid in the differential diagnosis of these pathologies becomes crucial. We performed an electronic search in PubMed, Web of Science and Scopus, without date or language restrictions, to identify all possible studies reporting D-dimer values in separate cohorts of children with MIS-C or Kawasaki disease. Three multicenter cohort studies were included in our analysis, totaling 487 patients (270 with MIS-C and 217 with Kawasaki disease). In this meta-analysis, significantly higher D-dimer values were found in MIS-C compared to Kawasaki disease in all three studies, yielding an SMD of 1.5 (95 % CI, 1.3–1.7) mg/L. Thus, very high D-dimer values early in the course of disease should raise the clinical suspicion of MIS-C rather than Kawasaki disease. Further studies should be planned to identify harmonized D-dimer diagnostic thresholds that may help discriminate these conditions. [ABSTRACT FROM AUTHOR]

Multisystemic inflammatory syndrome in children (MIS-C) is a rare, severe, post-infectious hyperinflammatory condition that occurs after COVID-19 infection. In this study, we aimed to demonstrate the risk reduction of MIS-C and severe MIS-C after Pfizer–BioNTech BNT162b2 mRNA COVID-19 vaccination. This nationwide cohort study included 526,685 PCR-confirmed COVID-19 cases (age < 19 years), of whom 14,118 were fully vaccinated prior to COVID-19 infection. MIS-C cases were collected from all hospitals in Israel from April 2020 through November 2021. The MIS-C rates were calculated among two COVID-19 populations: positive PCR confirmed cases and estimated COVID-19 cases (PCR confirmed and presumed). Vaccination status was determined from Ministry of Health (MoH) records. The MIS-C risk difference (RD) and 95% confidence intervals (95%CI) between vaccinated and unvaccinated patients are presented. Overall, 233 MIS-C cases under the age of 19 years were diagnosed and hospitalized in Israel during the study period. Among the estimated COVID-19 cases, MIS-C RD realistically ranged between 2.1 [95%CI 0.7–3.4] and 1.0 [95%CI 0.4–1.7] per 10,000 COVID-19 cases. For severe MIS-C, RD realistically ranged between 1.6 [95%CI 1.3–1.9] and 0.8 [95%CI 0.7–1.0], per 10,000 COVID-19 cases. Sensitivity analysis was performed on a wide range of presumed COVID-19 rates, demonstrating significant RD for each of these rates. Conclusion: This research demonstrates that vaccinating children and adolescents against COVID-19 has reduced the risk of MIS-C during the study period. What is Known: • Most of the published literature regarding vaccine effectiveness is based on case-control studies, which are limited due to small sample sizes and the inability to fully estimate the risk of MIS-C among vaccinated and unvaccinated children and adolescents. • The known underestimation of COVID-19 diagnosis among children and adolescents is challenging, as they often have few to no symptoms. What is New: • Significant risk difference was found in favor of the vaccinated group, even after including extreme assumptions regarding the underdiagnosed COVID-19 rate. • During this nationwide study period, it was found that vaccinating children and adolescents reduced the risk of MIS-C and its complications. [ABSTRACT FROM AUTHOR]

This document is a case report discussing a patient who presented with symptoms of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition associated with COVID-19. The patient experienced persistent fever, rash, gastrointestinal symptoms, and neurocognitive dysfunction. They were initially diagnosed with Still's Disease but did not respond to treatment. The patient was eventually diagnosed with MIS-C based on the CDC criteria and treated with intravenous immunoglobulin (IVIG) and methylprednisolone. The symptoms improved with treatment. The authors acknowledge the patient and her parents for giving permission to publish the details of the case. [Extracted from the article]

MIS-C is a rare, highly inflammatory state resembling incomplete Kawasaki disease, temporarily associated with COVID-19. The pathogenesis is not completely known. RNAseq was carried out on whole blood of six treatment-naïve MIS-C patients. This was compared against RNAseq transcriptomics data of five healthy controls (HC), four Kawasaki Disease (KD) and seven systemic Juvenile Idiopathic Arthritis (sJIA). Using PCA, MIS-C clustered separately from HC, KD and sJIA. Amongst the top 50 significant genes in the three comparisons with HC, KD, and sJIA, common genes were: TMCC2, ITGA2B, DMTN, GFI1B, PF4, QSER1, GRAP2, TUBB1. DSEA revealed that maximum number of hits for overexpressed pathways was for NABA matrisome activation when MIS-C was compared against HC. Cytokine stimulated cellular activation pathways, specifically IL-10 were downregulated. MIS-C had more activated pathways of neutrophil degranulation and acquired immune activation but less of coagulation system or heat-shock system involvement as compared to KD. As compared to sJIA, humoral immune response and complements were activated. Matrisome activation was higher, with increased cell–cell interaction and ECM signalling. This analysis revealed novel insights into the pathogenesis of MIS-C, including the potential role of matrisomes, humoral immune system and down-regulated interleukin-10 pathways. [ABSTRACT FROM AUTHOR]

The IFIH1 gene, encoding melanoma differentiation‐associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain‐of‐function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi–Goutieres and Singleton–Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID‐19 or multisystem inflammatory syndrome in children (MIS‐C) were identified with putative loss‐of‐function IFIH1 variants by whole‐exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL‐6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID‐19 or MIS‐C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS‐C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss‐of‐function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS‐CoV‐2‐related disorders. [ABSTRACT FROM AUTHOR]

Background. On December 2019, a novel coronavirus disease (COVID‐19) spread worldwide and became a pandemic. Multisystem inflammatory syndrome in children (MIS‐C) due to cytokine release syndrome following COVID‐19 presents with various manifestations. We hypothesize that one of the rare manifestations is acute abdomen. Case Presentation. In this case series, eight cases (five girls and three boys) of gastrointestinal (GI) involvement and acute abdomen were reported to be associated with the cytokine storm due to COVID‐19 infection. All patients were of Iranian nationality (Caucasian ethnicity), with a mean age of 8.9 years (range 3.5–14). They all presented with fever and acute abdominal pain. Additionally, maculopapular rash and edema of the extremities were common presentations. Free fluid on abdominal ultrasound or computerized tomography (CT) scan was observed in all patients. All cases tested positive for COVID‐19. In six cases, laparotomy or abdominal surgery was performed for a diagnosis of acute abdomen, but appendicitis was confirmed in only one case. None of the cases presented with phlegmon. Elevated serum lipase and amylase levels were noted in two cases. Seven patients received corticosteroid pulse therapy. Clinical symptoms improved after one or two doses, and all patients were discharged after 4 weeks of follow‐up with no mortality or morbidity. Conclusion. Patients experiencing unexplained acute abdominal pain along with fever, skin rash, and peripheral edema, who had a history of COVID‐19 infection prior to or during the episode of acute abdomen symptoms, should be considered to have MIS‐C. Furthermore, methylprednisolone pulse therapy could be a safe treatment option, reducing hospitalization duration in this patient population. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection can induce multisystem inflammatory syndrome in children, which resembles superantigen-induced toxic shock syndrome. Recent work has suggested that the SARS-CoV-2 spike (S) protein could act as a superantigen by binding T cell receptors (TCRs) and inducing broad antigen-independent T cell responses. Structure-based computational modeling identified potential TCR-binding sites near the S receptor-binding domain, in addition to a site with homology to known neurotoxins. We experimentally examined the mechanism underpinning this theory--the direct interaction between the TCR and S protein. Surface plasmon resonance of recombinantly expressed S protein and TCR revealed no detectable binding. Orthogonally, we pseudotyped lentiviruses with SARS-CoV-2 S in both wild-type and prefusion-stabilized forms, demonstrated their functionality in a cell line assay, and observed no transduction, activation, or stimulation of proliferation of CD8+ T cells. We conclude that it is unlikely that the SARS-CoV-2 spike protein engages nonspecifically with TCRs or has superantigenic character. [ABSTRACT FROM AUTHOR]

Introduction: Limited data are available regarding SARS-CoV-2 serological response dynamics in pediatric patients with COVID-19, contributing to gaps in our understanding of the immune response in this population. This study aimed to investigate SARS-CoV-2 IgG seropositivity in patients diagnosed with COVID-19 during hospitalization and 2-4 weeks after discharge. Methods: A cohort of patients, consisting of 31 individuals with confirmed acute COVID-19 infection and 27 diagnosed with Multisystem Inflammatory Syndrome in Children (MIS-C), was enrolled in the study. Follow-up clinic appointments were scheduled for 2-4 weeks post-discharge. During admission and follow-up, blood samples were collected from each patient for laboratory analysis. Anti-nucleoprotein SARS-CoV-2 IgG levels were determined using the Enzyme-Linked Immunosorbent Assay (ELISA) method. Results: In this study, a cohort of 58 patients was examined. At admission, 52% (n = 14) of MIS-C patients and 10% (n = 3) of acute COVID-19 patients had positive SARS-CoV-2 IgG test. Only 48 cases were referred to the hospital, and follow-up data was available for 20 cases with MIS-C and 28 cases with acute COVID-19. All patients (n = 15) who initially tested positive for SARS-CoV-2 IgG at admission remained positive serology during follow-up (100%). Among the 33 patients who initially tested negative, 12 (37.5%) showed a positive serology result during follow-up, while 21 (62.5%) remained negative. Within this subgroup, 11 cases (44%) were diagnosed with acute COVID-19, and one patient (12.5%) presented with MIS-C. Fourteen cases with acute COVID-19 infection (56%) and seven cases with MIS-C (87.5%) consistently showed negative serology results throughout the study. During follow-up, the median lymphocyte count demonstrated a significant difference, with 0.96 x 109 cells per L (IQR: 0.75-3.0 x 109 cells per L) in the SARS-CoV-2 IgG-negative group and 2.9 x 109 cells per L (IQR = 1.33-7.22 x 109 cells per L) in the SARS-CoV-2 IgG-positive group (p-value = 0.03). Patients who demonstrated seropositivity during the follow-up were associated with a notably severe disease (p-value = 0.028). Conclusion: Our study highlights the dynamic nature of SARS-CoV-2 IgG antibody responses in pediatric patients with COVID-19 infection. We observed a notable increase in seropositivity rates during follow-up. Furthermore, patients who were seropositive at follow-up demonstrated a severe disease course and lower lymphocyte counts compared to those with persistently negative serology. Our findings underscore the importance of longitudinal serological monitoring in understanding disease progression and immune response dynamics in pediatric COVID-19 cases. [ABSTRACT FROM AUTHOR]

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) has emerged as a severe pediatric complication during the SARS-CoV-2 pandemic, with potential long-term cardiovascular repercussions. We hypothesized that heart rate and blood pressure control at rest and during postural maneuvers in MIS-C patients, months after the remission of the inflammatory syndrome, may reveal long-term autonomic dysfunctions. Methods: We assessed 17 MIS-C patients (13 males; 11.9 ± 2.6 years, m ± SD) 9 months after acute infection and 18 age- (12.5 ± 2.1 years) and sex- (13 males) matched controls. Heart rate and blood pressure variability, baroreflex function, and hemodynamic parameters were analyzed in supine and standing postures. Results: MIS-C patients exhibited reduced heart rate variability, particularly in parasympathetic parameters during standing (pNN50+: 6.1 ± 6.4% in controls, 2.5 ± 3.9% in MIS-C; RMSSD: 34 ± 19 ms in controls, 21 ± 14 ms in MIS-C, p < 0.05), with no interaction between case and posture. Blood pressure variability and baroreflex sensitivity did not differ between groups except for the high-frequency power in systolic blood pressure (3.3 ± 1.2 mmHg2 in controls, 1.8 ± 1.2 mmHg2 in MIS-C, p < 0.05). The MIS-C group also showed lower diastolic pressure–time indices (DPTI) and systolic pressure–time indices (SPTI), particularly in standing (DPTI: 36.2 ± 9.4 mmHg·s in controls, 29.4 ± 6.2 mmHg·s in MIS-C; SPTI: 26.5 ± 4.3 mmHg·s in controls, 23.9 ± 2.4 mmHg·s in MIS-C, p < 0.05). Conclusions: Altered cardiovascular autonomic control may persist in MIS-C patients with, however, compensatory mechanisms that may help maintain cardiovascular homeostasis during light autonomic challenges, such as postural maneuvers. These results highlight the importance of assessing long-term cardiovascular autonomic control in children with MIS-C to possibly identify residual cardiovascular risks and inform targeted interventions and rehabilitation protocols. [ABSTRACT FROM AUTHOR]

Multisystem inflammatory syndrome in children (MIS-C) is a disease that made its mark in the early days of the COVID-19 pandemic due to the diverse course and symptoms affecting multiple body systems. It is a condition that develops in pediatric patients about 2–6 weeks after contact with a person infected with the SARS-CoV-2 virus. In many instances, MIS-C has caused multiple organ failure, with particularly severe complications involving the cardiovascular system and manifesting as hypotension, various cardiac arrhythmias, myocarditis or coronary artery lesions resembling those seen in Kawasaki disease. Currently, the incidence of MIS-C is about 1–3 per 1000 children, with a decreasing trend in recent years due to the introduction of immunization against the SARS-CoV-2 virus for children as young as 6 months. In our paper, we present the case of a patient with a severe course of MIS-C with numerous cardiovascular and neurological complications, in whom the symptoms of the disease were managed by administering biological treatment. We also present a review of the literature on the subject, which shows how many different facets this disease can have and that physicians still need to remain alert, as there are cases of severe MIS-C, especially in unvaccinated patients. [ABSTRACT FROM AUTHOR]

Background: Multisystem inflammatory syndrome in children (MIS-C) is an uncommon condition linked to SARS-CoV-2, the virus responsible for COVID-19. Typically emerging 2-6 weeks after a child contracts the virus, MIS-C leads to inflammation in various organs, including the heart, kidneys, lungs, brain, skin, and gastrointestinal tract. Objective: To assess the cardiac affection, management and outcome in MIS-C patients. Patients and methods: This analytical cross-sectional study was carried out in Cairo University Children Hospital and included 28 patients, diagnosed with MIS-C post COVID. All patients were subjected to complete history taking, through general, cardiac examination and echocardiographic assessment. Results: Males were the most commonly presented gender accounting for 71.4%, while females were 28.6%. Fever was the most commonly presented symptom (96.4%). Cardiac affection was found in 22 (78.6 %) patients by cardiac echocardiography and coronary dilatation was the most common finding by echocardiography in 18 (64.3%) patients. The most common was left coronary artery dilatation in 16 (57.1%) patients, followed by right coronary artery in 8 (28.6%) patients while only 2 (7.1%) had coronary artery aneurysm. All patients in the current study received intravenous immunoglobulin G (IVIG) for 2 days while 14 (50%) patients received pulse steroids followed by oral steroids after IVIG course. Conclusion: Cardiac affection is common in MIS-C patients and must be looked for. The most common presentation is coronary artery dilatation; mostly left coronary artery so early and appropriate intervention is essential to avoid complications. [ABSTRACT FROM AUTHOR]

Background: Multisystem inflammatory syndrome in children (MIS-C) is an uncommon illness related with SARS-CoV-2. It generally develops 2-6 weeks after a kid is infected with SARS-CoV-2 and affects many body organs that become inflamed. Objective: This study aimed to investigate the clinical manifestation of multisystem inflammatory syndrome and the effectiveness of different therapeutic modalities. Patients and methods: A prospective cross-sectional observational study was conducted among 75 children with multisystem inflammatory syndrome in Pediatric, Neonatal Intensive Care Unit, Intermediate Care Unit, and Emergency Department at Sohag University Hospital (From June 2022 to February 2024) included 55 confirmed cases and 20 suspected cases. Results: Regarding the reported symptoms, all confirmed cases complained of fever and half of them complained of pulmonary symptoms. 56.4% of cases complained of diarrhea and 1.8% of cases complained of colic. Regarding clinical signs, 45.5% of cases were hypotensive and 52.7% of cases complained of tachypnea. The mean temperature was 38.91 ± 0.49 °C. Regarding heart examination, 50.9% of cases complained of tachycardia. Regarding therapeutic modalities, 36.4% of cases needed combination of antibiotic, solumedrol and IVIG and most of cases (85.5%) received anticoagulants. Conclusion: Early diagnosis and management through routine screening for MIS-C in pediatric patients presenting with prolonged fever, gastrointestinal, respiratory, or cardiovascular symptoms, especially with a history of COVID-19 exposure. Clinical protocols included standardized treatment protocols for MIS-C to ensure timely and effective management. [ABSTRACT FROM AUTHOR]

This study aimed to describe the characteristics of multisystemic inflammatory syndrome associated with COVID-19 (MIS-C) in the first three years of the pandemic in children in a pediatric hospital in Peru. We conducted an observational, descriptive study with data from 73 patients and described the clinical and laboratory characteristics, treatment and complications according to the wave of the pandemic and whether they had shock. The median age was 6 years, gastrointestinal and mucocutaneous manifestations were frequent in the three waves. Kawasaki disease-like phenotype was present in 34 (46.6%) patients and 21 (28.8%) patients developed shock. The most commonly used treatment was immunoglobulin (95.9%), followed by acetylsalicylic acid (94.5%) and corticosteroid (86.3%). Five (7%) patients had coronary aneurysm and 17 (23.3%) were admitted to the intensive care unit (ICU). Patients with shock had greater laboratorial alteration and need for mechanical ventilation. In conclusion, MIS-C has decreased in the first three years of the pandemic, possibly due to COVID-19 vaccination in children. [ABSTRACT FROM AUTHOR]

Aim: Multisystem Inflammatory Syndrome in Children (MIS-C) is a disease developed after about eight weeks of the new coronavirus disease (COVID-19) infection in children. The underlying reason for MIS-C is still unknown. This study aims to assess the nasopharyngeal expressions of Angiotensin-converting enzyme 2 (ACE2), the differentiation 147 receptor cluster (CD147), and the transmembrane serine protease 2 (TMPRSS2) receptors in the MIS-C population. Since these receptors are related to COVID-19 infection, children with previous COVID-19 history were included as a control group. This study is essential for future studies to see if there is any significant expression difference between these receptors in control and MIS-C populations. Materials and Methods: The prospective cohort study took place at Ondokuz Mayıs University. The participants of this study consisted of patients aged 0-18 years who were diagnosed with MIS-C due to COVID-19 infection or patients with only previous COVID- 19 pneumonia but without MIS-C development. A total of 79 cases were registered in this study. Nasopharyngeal samples of children were collected. Total RNA was isolated from all samples. The expression of ACE2, CD147, and TMPRSS2 genes was accessed by real-time quantitative PCR (RT-qPCR). Results: Nasopharyngeal expression of CD147 and TMPRSS2 were not changed in COVID-19 (n=42) and MIS-C (n=37) cases. Expression of ACE2 was increased in the under 10-year-old MIS-C group (n=23) (p=0.004381). Conclusion: Future studies may exclude the nasopharyngeal expression of CD147 and TMPRSS2 to develop MIS-C. Further investigations are required to learn how ACE2 expression contributes to MIS-C development. [ABSTRACT FROM AUTHOR]

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be more infectious and less severe than the other variants. Despite the increasing number of symptomatic patients, severe neurological complications in children with the Omicron variant have been reported rarely, unlike with wild-type or Delta variants. This study aimed to investigate severe neurological complications in children with Omicron variant infection. We conducted a retrospective study of 17 pediatric patients with severe neurological manifestations associated with coronavirus disease 2019 in Korea during the Omicron variant prevalence, from January 1 to April 30, 2022. Among the 17 patients, 11 had pre-existing neurological disabilities and nine met the criteria for multisystem inflammatory syndrome in children (MIS-C). Four of the five vaccine-eligible patients (12 years and older) were unvaccinated. Severe neurological manifestations included acute necrotizing encephalopathy, acute fulminant cerebral edema, acute disseminated encephalomyelitis, basal ganglia encephalitis, unclassified severe encephalopathy/encephalitis, and refractory status dystonicus. Patients with MIS-C and underlying neurological disabilities had longer median hospital and intensive care unit stays compared with those without these conditions. Five patients survived with new neurological deficits at the one-year follow-up, and three died, all of whom had underlying neurological disabilities. This study shows that severe neurological complications in pediatric patients with the Omicron variant of SARS-CoV-2 occur infrequently but may lead to significant morbidity and mortality, especially among those with pre-existing neurological disabilities and unvaccinated individuals. Continued efforts are necessary to prevent and manage such complications in these vulnerable populations. [ABSTRACT FROM AUTHOR]

We describe 5 children who had Rocky Mountain spotted fever (RMSF) and manifested clinical symptoms similar to multisystem inflammatory syndrome in Sonora, Mexico, where RMSF is hyperendemic. Physicians should consider RMSF in differential diagnoses of hospitalized patients with multisystem inflammatory syndrome to prevent illness and death caused by rickettsial disease. [ABSTRACT FROM AUTHOR]

Objective: The objective is to expose the cardiovascular alterations in patients diagnosed with pediatric inflammatory multisystem syndrome (PIMS) associated with COVID-19 during the SARS-CoV-2 pandemic, in order to understand the disease, its evolution, and optimal management upon diagnosis. Method: Retrospective, observational, cross-sectional analytical study of patients diagnosed with PIMS according to the criteria of the World Health Organization at the National Institute of Pediatrics, from March 2020 to December 2021. Results: During the study period, 77 patients with PIMS were diagnosed. The results showed correlation between the shock state and alteration of laboratory markers (platelets 144217.29 ± 139321.6 µL [p < 0.001], procalcitonin 27.37 ± 38.37 ng/ml [p = 0.05] and ferritin 1937.87 ± 2562.63 [p < 0.001]). The ventricular function in patients with shock was significantly lower compared to those without shock (49.6 ± 9.1% vs. 58.1 ± 8.4 %; t-Student p < 0.001), as well as injury to the left coronary artery (p = 0.02). There is a correlation between NT-proBNP and ventricular dysfunction (Kruskal-Wallis p = 0.007). Statistical significance was found in the association between death, elevation of inflammatory markers and ventricular dysfunction (p < 0.001). Conclusions: The cardiovascular alterations observed, in order of frequency, were pericardial effusion (25.7%), myocarditis (15%), mild ventricular dysfunction (13.5%) and small coronary aneurysm with predominance of the left coronary artery and the anterior descending one. [ABSTRACT FROM AUTHOR]

Objective In this study, our objective is to compare the demographic, clinical, laboratory, and echocardiographic findings of patients with multisystem inflammatory syndrome in children (MIS-C) and Kawasaki's disease (KD) diagnosed in the prepandemic period. Methods We retrospectively collected data from all pediatric patients who met the Centers for Disease Control and Prevention's MIS-C case definition and who met the American Heart Association's definition of complete KD before the coronavirus disease 2019 pandemic. Results A total of 37 patients diagnosed with MIS-C and 40 patients diagnosed with complete KD were included. Gastrointestinal findings were significantly higher in the MIS-C group than in the KD group (vomiting [ p = 0.009], diarrhea [ p = 0.009]). The incidence of thrombocytopenia (48.6%) was significantly higher in the MIS-C group. Regarding inflammatory markers, procalcitonin and ferritin were significantly higher in the MIS-C group (p = 0.032 and p = 0.006) and the erythrocyte sedimentation rate was higher in the KD group (p < 0.001). Pericardial effusion and mitral valve regurgitation were significantly more frequent in the MIS-C group (p = 0.024 and p = 0.001). Conclusion Although they have similar findings, our current study findings show that MIS-C and KD differ from each other with different clinical and laboratory features. We think that these differences will help clinicians in diagnosis and patient management. [ABSTRACT FROM AUTHOR]

The cardiac biomarkers high sensitivity cardiac troponin I (hs-cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are utilised in paediatric healthcare for the diagnosis and prognostic assessment of many conditions including myocarditis, congenital heart disease, multisystem inflammatory syndrome in children (MIS-C) and heart failure. However, the standardised age-related reference intervals, 99th percentile cut-offs and clinical guidelines are not available, making the interpretation of these biomarkers challenging. This study aimed to generate normative data in a paediatric cohort for the Siemens Atellica® IM 1300 analyser. Residual plasma samples were collected from children aged up to 17 years attending primary care and out-patient settings and with no apparent evidence of cardiac dysfunction, renal dysfunction or other confounders. Reference intervals were generated using the 2.5th–97.5th percentiles, and 99th percentile cut-offs determined according to CLSI EP28-A3c. Statistical analysis revealed that partitioning was not required for gender for either biomarker. The reference interval for hs-cTnI for children aged one month to 16 years (n=292, 146 females and 146 males) was <14 ng/L with a 99th percentile cut-off of 19 ng/L. The reference interval for NT-proBNP for children aged one month up to one year was <714 ng/L (n=14) and for children aged 1–16 years (n=339) was <295 ng/L. This is the first paediatric reference interval data generated on the Siemens Atellica® solution. These reference intervals and 99th percentiles will inform clinical decisions in the paediatric cardiology setting. [ABSTRACT FROM AUTHOR]

The clinical presentation, organ involvement, and severity of disease caused by SARS-CoV-2 are highly variable, ranging from asymptomatic or mild infection to respiratory or multi-organ failure and, in children and young adults, the life-threatening multisystemic inflammatory disease (MIS-C). SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 receptor (ACE-2), which is expressed on the cell surfaces of all organ systems, including the gastrointestinal tract. GI manifestations have a high prevalence in children with COVID-19. However, isolated terminal ileitis without other manifestations of COVID-19 is rare. In March 2023, two previously healthy boys (aged 16 months and 9 years) without respiratory symptoms presented with fever and diarrhea, elevated C-reactive protein levels, and low procalcitonin levels. Imaging studies revealed marked terminal ileitis in both cases. SARS-CoV-2 (Omicron XBB.1.9 and XBB.1.5 variants) was detected by nucleic acid amplification in throat and stool samples. Both patients recovered fast with supportive measures only. A differential diagnosis of acute abdominal pain includes enterocolitis, mesenteric lymphadenitis, appendicitis, and more. During SARS-CoV-2 epidemics, this virus alone may be responsible for inflammation of the terminal ileum, as demonstrated. Coinfection with Campylobacter jejuni in one of our patients demonstrates the importance of a complete microbiological workup. [ABSTRACT FROM AUTHOR]