Inflammatory Syndrome In Children Research Articles

The Complex Landscape of Immune Dysregulation in Multisystem Inflammatory Syndrome in Children with COVID-19

Abstract The immune responses following SARS-CoV-2 infection in children are still under investigation. While coronavirus disease 2019 (COVID-19) is usually mild in the pediatric population, some children develop severe clinical manifestations or multisystem inflammatory syndrome in children (MIS-C) after infection. MIS-C, typically emerging 2-6 weeks after SARS-CoV-2 exposure, is characterized by a hyperinflammatory response affecting multiple organs. This review aims to explore the complex landscape of immune dysregulation in MIS-C, focusing on innate, T cell-, and B cell-mediated immunity, and discusses the role of SARS-CoV-2 spike protein as a superantigen in MIS-C pathophysiology. Understanding these mechanisms is crucial for improving the management and outcomes for affected children.

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.

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. • 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. • 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.

Mucocutaneous manifestation of COVID-19 infection in pediatrics age groups

Background and objectives: It is known that the COVID-19 virus can induce a wide range of mucocutaneous symptoms. This study's main goal is to describe the variety of cutaneous symptoms caused by COVID-19 in the pediatric age category. Methods: This is a retrospective case series study of pediatric patients with COVID-19 infection who were admitted to Jamal Ahmad Rashid Pediatrics Teaching Hospital in Sulaimaniyah city from September 2021 to March 2022. Moderate to severe Covid-19 infection was a factor in the patients' admissions. The patient’s complete medical history was reviewed, which should include their age, gender, and any mucocutaneous manifestations, as well as their past medical history, family history. Results: Three hundred twenty three cases of COVID-19 infection were enrolled in this study, 36 of them had skin manifestations. There were 56% female and 44% males. Their ages ranged from zero to 13 years. Skin manifestations were 13 patients (36%) had erythematomaculopapular rash, 8 patients (22%) had vesicular lesions, 7 patients (19%) had chilblain, 6 patients (17%) had urticaria and 2 patients (6%) had erythema multiforme. Overall 41 patients had Multisystem inflammatory syndrome in children (MIS-C), 11 patients had cutaneous manifestations (6 patients had erythematomaculopapular rash, 5 patients had vesicular rash), and 6 patients had mucosal lesions (4 patients had conjunctivitis, 2 patients had oral lesions). Conclusions: We found that despite pulmonary and other systemic manifestation also corona virus infection can cause many mucocutaneoues manifestation in pediatrics age groups.However, further studies with larger samples size and longer duration is recommended.

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

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). 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. 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. 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.

The Spectrum of Postacute Sequelae of COVID-19 in Children: From MIS-C to Long COVID.

The effects of SARS-CoV-2 infection on children continue to evolve following the onset of the COVID-19 pandemic. Although life-threatening multisystem inflammatory syndrome in children (MIS-C) has become rare, long-standing symptoms stemming from persistent immune activation beyond the resolution of acute SARS-CoV-2 infection contribute to major health sequelae and continue to pose an economic burden. Shared pathophysiologic mechanisms place MIS-C and long COVID within a vast spectrum of postinfectious conditions characterized by intestinal dysbiosis, increased gut permeability, and varying degrees of immune dysregulation. Insights obtained from MIS-C will help shape our understanding of the more indolent and prevalent postacute sequelae of COVID and ultimately guide efforts to improve diagnosis and management of postinfectious complications of SARS-CoV-2 infection in children.

Role of Macrophage Migration Inhibitory Factor in Prediction of Cardiac Affection in Multisystem Inflammatory Syndrome in Children

Role of Macrophage Migration Inhibitory Factor in Prediction of Cardiac Affection in Multisystem Inflammatory Syndrome in Children

Echocardiograms and bed placement in patients with multisystem inflammatory syndrome in children.

Understanding of multisystem inflammatory syndrome in children (MIS-C) continues to evolve with extensive evaluations, including echocardiograms, obtained in emergency departments (EDs) to assist with clinical decision making and bed allocation. We assessed the utility of obtaining echocardiograms in the ED to assist in determining bed placement for this patient population. This 2-year retrospective single-center study of patients 0-21 years old without underlying cardiac disease hospitalized for MIS-C focused on individuals whose initial evaluation occurred in the institution's ED and whose echocardiogram was obtained either in the ED or within 24 hours of admission. Patients were placed in two cohorts-those remaining in their unit of admission without transfer (cohort WoT) and those transferred (cohort T) from their initial unit to one with a differing level of care within 24 hours. Pearson chi-square test assessed the relationship between echocardiogram status and appropriate bed placement, defined as no transfer within 24 hours. Of the 60 patients who met study criteria, no significant difference was detected in rates of transfer between patients whose echocardiograms were obtained in the ED versus those obtained within 24 hours of admission (odds ratio =2.08; 95% confidence interval: 0.58, 7.95; P=0.28). Cardiac involvement is a known complication of MIS-C; however, our study yields no evidence in favor of obtaining echocardiograms in the ED to ensure appropriate bed placement. While this modality remains integral in evaluation and management, it does not appear to be requisite as part of an emergent workup prior to admission.

The Role of Intestinal Epithelial Permeability in Multisystem Inflammatory Syndrome in Children: A Case–Control Study

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.

Interplay between Multisystem Inflammatory Syndrome in Children, Interleukin 6, Microbiome, and Gut Barrier Integrity

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.

An opportunity missed: Strengthening health system data on multisystem inflammatory syndrome in children from low- and middle-income countries in Asia

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a severe complication associated with SARS-CoV-2 infection. The clinical epidemiology of MIS-C is not completely understood in low- and middle-income countries (LMICs) due to limited reporting, including in Asia where there was a substantial burden of COVID-19. We aimed to discuss the challenges of diagnosing MIS-C and factors which may cause children from Asian LMICs to have an increased risk of MIS-C. MethodsNot applicable. ResultsThe burden of MIS-C in Asian LMICs may be disproportionately high due to underlying risk factors, resource-limited health systems, and the increased infectivity and transmissibility of recent SARS-CoV-2 variants. Complex clinical features of MIS-C contributed to missed or delayed diagnosis and treatment, while underlying risk factors including ethnicity, chronic health conditions, and socioeconomic factors may have predisposed children in Asian LMICs to MIS-C. ConclusionsThere was a lack of data on the clinical epidemiology of MIS-C in Asian LMICs during the COVID-19 pandemic, despite reports of higher paediatric mortality rates compared to high-income countries. This highlights the need for LMICs to have strong surveillance systems to collect high-quality and timely data on newly emerging complications associated with a pandemic, such as MIS-C. This will lead to rapid understanding of these emerging complications, and inform clinical management, disease prevention and health system planning.

Long-term Health Outcomes After Hospital Discharge Among Children Hospitalized for MIS-C or COVID-19, September 29, 2021, to June 21, 2022.

The long-term effects of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) or acute COVID-19 are not well known. Our objective was to determine long-term outcomes. Children hospitalized with MIS-C or COVID-19 at 3 US hospitals from March 2020, through February 2021 were followed to assess health through 2 years post-hospitalization using medical records and patient surveys. Medical record abstraction was performed for 183 patients hospitalized with MIS-C, 53 of whom participated in surveys, and 97 patients hospitalized with COVID-19, 35 of whom participated in surveys. Patients with MIS-C were younger (median, 9 vs. 14 years of age for COVID-19 patients; P = 0.004), more frequently male (62% vs. 39%; P < 0.001) and had more cardiac (14% vs. 2%; P = 0.001) and neurologic sequelae (8% vs. 1%; P = 0.023). Children with COVID-19 more often had other comorbidities (59% vs. 19%; P < 0.001). Full mental recovery at the time of survey 2 (median, 16 months post-hospitalization for patients with MIS-C and 20 months for patients with COVID-19) was 85% and 88%, respectively; full physical recovery was 87% and 81%, respectively; and nearly all had resumption of normal activities. Patients with MIS-C reported more frequent headache at 1 month (45% vs. 20%; P = 0.037). Patients with COVID-19 were more likely to report cough at 1 month (37% vs. 17%; P = 0.045). Fatigue persisted >1 year in 15%-20% of patients in both groups. Approximately 20% of children with MIS-C and COVID-19 continued to have symptoms including fatigue and headache >1 year after hospital discharge. The duration of these findings emphasizes the importance of providers following patients until sequelae have resolved.

Hospitalizations for Multisystem Inflammatory Syndrome in Children (MIS-C) in US Children’s Hospitals in 2023 vs 2021

This cross-sectional study evaluates hospitalizations for multisystem inflammatory syndrome in children in US pediatric hospitals in 2023 vs 2021.

Clinical Significance of B-Type Natriuretic Peptide and N-Terminal Pro-B-Type Natriuretic Peptide in Pediatric Patients: Insights into Their Utility in the Presence or Absence of Pre-Existing Heart Conditions.

The clinical significance of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients remains an area of evolving understanding, particularly regarding their utility in the presence or absence of pre-existing heart conditions. While clear cutoff values and established roles in heart failure are understood in adult patients, pediatric norms vary with age, complicating interpretation. Notably, the emergence of multi-system inflammatory syndrome in children (MIS-C) has highlighted the importance of these markers not only in the detection of acute heart failure but also as a marker of disease severity and even as a differential diagnosis tool. This review summarizes current knowledge on the utility of BNP and NT-proBNP in pediatric patients. Their unique physiology, including circulation and compensation mechanisms, likely influence BNP and NT-proBNP release, potentially even in non-heart failure states. Factors such as dynamic volemic changes accompanying inflammatory diseases in children may contribute. Thus, understanding the nuanced roles of BNP and NT-proBNP in pediatric populations is crucial for the accurate diagnosis, management, and differentiation of cardiac and non-cardiac conditions.

Multisystemic Inflammatory Syndrome in Children (MIS-C) With COVID-19 and Kidney Involvement: Poor Outcomes in a Case Series.

Multisystemic inflammatory syndrome (Mis-C) has emerged in May 2020 as a serious complication of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). A total of 6 children presented to tertiary care hospitals with Mis-C, of which 5 (83%) have died during hospitalization. All included patients presented with respiratory symptoms (ranged from mild to severe acute respiratory distress syndrome) and gastrointestinal symptoms. Most of the patients are known to have medical illnesses. Pediatric Risk of Mortality (PRISM) IV score ranged from 3 to 87. All patients developed acidosis and varying stages of acute kidney injury and electrolyte disturbances. All were treated for coagulopathy, thrombocytopenia, bacterial infections as well as antiviral medications (either ritonavir or lopinavir). Most patients had chest X-ray changes either unilateral or bilateral lung changes. Multisystemic inflammatory syndrome is a rare, yet serious complication of SARS-CoV2 infection in children. Multisystem involvement should be anticipated and promptly treated.

Molecular mimicry in multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Multisystem inflammatory syndrome in children across 16 Latin American countries: A multicenter study from the REKAMLATINA Network

ObjectivesOur aim was to describe the epidemiology and outcomes of multisystem inflammatory syndrome in children (MIS-C) in Latin America. MethodsWe conducted an observational, retrospective, and prospective multicenter study that gathered information from 84 participating centers across 16 Latin American countries between August 1, 2020 and June 30, 2022. ResultsOf the 1239 reported children with MIS-C, 84.18% were previously healthy. The most frequent clinical manifestation in our studied population was abdominal pain (N = 804, 64.9%), followed by conjunctival injection (N = 784, 63.3%). The median duration of fever at the time of hospital admission was 5 days and a significant number of subjects required admission to an intensive care unit (N = 589, 47.5%). Most of the subjects (N = 1096, 88.7%) were treated with intravenous immunoglobulin, whereas 76.7% (N = 947) were treated with steroids, of whom 10.6% (N = 100) did not receive intravenous immunoglobulin. The death rate attributed to MIS-C was 4.88%, with a rate of 3.39% for those initially diagnosed with MIS-C and 8.85% for those whose admission diagnosis was not MIS-C (P <0.001, odds ratio 2.76, 95% confidence interval 1.6-4.6). ConclusionsOne of the most significant findings from our study was the death rate, especially in those not initially diagnosed with MIS-C, in whom the rate was higher. This highlights the importance of increasing awareness and making an earlier diagnosis of MIS-C in Latin America.

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

Understanding the relevance of immunological markers in severe multisystem inflammatory syndrome in children through machine learning

Objectives: Multisystem inflammatory syndrome in children (MIS-C) is a late manifestation of SARS-CoV-2 infection, which presents with symptoms ranging from milder mucocutaneous and gastrointestinal symptoms to severe cardiovascular and neurological manifestations. We studied the clinical, biochemical, hematological, and immunological characteristics of MIS-C patients to understand this disease entity and to identify markers of severe disease. Materials and Methods: Twenty-four MIS-C patients, four acute COVID-19 infections, and ten healthy controls (HC) from a tertiary care pediatric hospital in Mumbai were enrolled in the study. Clinical, biochemical, hematological, and immunological parameters comprising major lymphocyte, neutrophil, and monocyte subpopulations and key activator and inhibitory markers were studied. Statistical Analysis: All parameters were compared between the healthy, COVID and MIS-C groups at Day 0, 7 and 14 using non-parametric statistical tests. Machine learning tools were used for multivariate data analysis to identify the immunological parameters that could help predict severe disease. Results: NKp46pos NK cell (%), CD11 positive eosinophil (%), D-dimer, and Tim3pos Tc (%) were identified as the most important markers that could help predict severe disease, with NKp46pos NK cells as the top contributor. A disease severity metric utilizing these markers can be used to identify patients who are likely to have a severe course of disease. Conclusions: NK cells directly contribute to disease severity in MIS-C. As the JAK-STAT pathway is known to be important for NK cell development, maturation, and function, ruxolitinib, which is a JAK1/JAK2 inhibitor, might be beneficial in the management of this condition.

Systemic Arterial Function after Multisystem Inflammatory Syndrome in Children Associated with COVID-19

Systemic Arterial Function after Multisystem Inflammatory Syndrome in Children Associated with COVID-19

SARS-CoV-2 spike does not interact with the T cell receptor or directly activate T cells

SARS-CoV-2infection 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.