Multisystem Inflammatory Syndrome In Children Research Articles

Consequences beyond acute SARS-CoV-2 infection in children.

Although most children are spared from developing complications from SARS-CoV-2 infection, some may suffer consequences including Long Covid and multisystem inflammatory syndrome in children (MIS-C). Although the occurrence of these conditions has decreased over time, they can still occur, and recognition of symptoms and prompt diagnosis is imperative for early intervention.

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

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

Characteristics of Multisystem Inflammatory Syndrome in Children Across COVID-19 Variants in Vojvodina

Background/Objectives: To investigate if the severity and presentation of multisystem inflammatory syndrome in children (MIS-C) vary between different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Methods: This retrospective study included 59 patients aged 0–18 years, diagnosed with COVID-19 and MIS-C, treated and monitored over a one-year period after discharge from hospital. The patients were grouped according to the predominant SARS-CoV-2 variant. The predominant variant of SARS-CoV-2 was assumed by the date of hospitalization. The following patient data were collected: demographic data (age, sex), information on comorbidities, body mass index, clinical data (fever and duration of febrile periods, symptoms of Kawasaki-like phenotypes, and presence of respiratory, cardiovascular, gastrointestinal, neurological and other symptoms), and laboratory and imaging findings. Results: In total, 24 (41%), 19 (32%), and 15 (25%) patients were diagnosed with MIS-C during the Alpha, Delta, and Omicron periods, respectively (63.8% were males; 36.2% were females). Comorbidities were present in 49% of patients. Respiratory symptoms were the most common during the Delta period (73%, p = 0.028). There was no statistically significant difference in the occurrence of other symptoms, laboratory findings, treatment, complications, and long-term outcomes between groups. Conclusions: No significant correlation was found between hospitalization date (used to estimate COVID-19 variant) and presentation/severity of MIS-C.

Multisystem Inflammatory Syndrome of Adults (MIS-A) as Delayed Severe Presentation of SARS-CoV-2 Infection: A Description of Two Cases

Background: SARS-CoV-2 infection can lead to a potentially life-threatening condition known as SARS-CoV-2-associated multisystem inflammatory syndrome in children (MIS-C), which differs from the severe lung disease and thrombotic complications commonly seen in adults. Recently, similar cases have been identified in adults, characterized by a clinical multisystem inflammatory syndrome referred to as MIS-A, which can emerge as a late and severe complication of SARS-CoV-2 infection. Case Presentation: We report two cases of MIS-A that were recently admitted to our hospital. Both patients developed a severe multisystem inflammatory syndrome despite experiencing only mild SARS-CoV-2 infection. Key clinical features in both cases included significant systemic inflammation, prominent cardiac involvement, and thrombocytopenia. Prior SARS-CoV-2 infection was confirmed through serological testing. Treatment protocols for MIS-C, including steroids and immunoglobulins, proved effective for both patients. Conclusions: Clinicians should remain vigilant for MIS-A in the context of ongoing SARS-CoV-2 infection worldwide. This infection, even when presenting with mild or no symptoms, can progress to a life-threatening hyperinflammatory syndrome with cardiac implications if not promptly recognized and treated.

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

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

Multisystem Inflammatory Syndrome in Children (MIS-C) in a Lithuanian Paediatric Tertiary Care Center

Background and Objectives: Due to its link with the SARS-CoV-2, Multisystem Inflammatory Syndrome in Children (MIS-C) gained global attention as a serious condition that requires hospital care. Our study aimed to present the clinical and laboratory characteristics of MIS-C patients by age group and intensive care unit (ICU) admission status and assess early echocardiographic changes. Materials and Methods: A single-center partly retrospective, partly prospective observational cohort study was performed from December 2020 to June 2024. The study included 42 patients aged between 1 month and 18 years who were diagnosed with MIS-C and gave informed consent. Results: The median age was 6.5 years (IQR 2.0–9.3). The predominant symptoms were cardiovascular (88.1%), mucocutaneous (85.7%) and gastrointestinal (76.2%). Five children (11.9%) developed shock. About two-thirds of patients (66.7%) were admitted to the ICU. Adolescents (≥12 years) were less likely to exhibit mucocutaneous or cardiovascular symptoms and thus less frequently having Kawasaki—like disease symptoms compared with other age groups (<5 years or 5–11 years). Lymphopenia was more common among patients aged 5 years and older. Adolescents had higher procalcitonin (PCT) and a lower estimated glomerular filtration rate. Troponin I and B-type natriuretic peptide (BNP) levels were higher in children aged 5–11 years, while ferritin levels were lower among the youngest (<5 years). Patients treated at the ICU were more likely to have cardiovascular and respiratory symptoms, as well as a history of symptomatic COVID-19, higher C-reactive protein (CRP), PCT, BNP and lower albumin levels. Echocardiographic abnormalities were found in 71.4% of cases. During hospitalization, left ventricular ejection fraction values increased significantly (p < 0.001) over 12 (IQR 9.0–14.0) days. Conclusions: Symptoms and laboratory markers of MIS-C vary according to age. Higher CRP, PCT, BNP and hypoalbuminemia are predictors of MIS-C severity. Cardiovascular involvement is common and might be severe, but rapid resolution is encouraging.

Relationship between thyroid function and lipid atherogenic profile in pediatric patients with multisystem inflammatory syndrome associated with COVID-19.

Concurrent alterations in the metabolic profile and thyroid dysfunction, including non-thyroidal illness syndrome (NTIS) has been reported in multisystem inflammatory syndrome in children (MIS-C). Considering the influence of thyroid hormones (TH) on lipid metabolism, we explored the relationship between thyroid function and the atherogenic lipid profile in children with MIS-C at admission and during a 12-month follow-up. we considered children admitted for MIS-C. Total and HDL cholesterol, triglycerides (TG), fasting plasma glucose, fasting plasma insulin as well as free T3 (FT3), free T4 (FT4), and TSH were assessed at diagnosis within 24 h of admission and during follow-up. TG/HDL ratio, no-HDL/HDL ratio and atherogenic index of plasma was also considered as atherogenic risk markers. we monitored 56 children. On admission, pathological levels of FT3, FT4, TSH, TG, TC, HDL, TG/HDL ratio, no-HDL/HDL ratio, and AIP were detected. Correlation analyses revealed associations between FT3, FT4, and lipid markers and TSH with TG. During monitoring, while complete restoration of TH balance was achieved at 12 months, some patients still exhibited an altered lipid profile, without correlation between thyroid function and lipid markers. we supported a relationship between thyroid function and an atherogenic lipid profile in children with MIS-C. This may result from interactions between adaptive and innate metabolic responses and genetic predisposition. Elucidating the relationship between TH and metabolic pathways during infections could help identify new biomarkers to prevent acute and fatal outcomes, improving patient prognosis and protecting long-term health.

Cutaneous Manifestations of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C)

Background: Characteristics of dermatological manifestations are frequently encountered in pediatric COVID-19, similar to the presentation in multisystem inflammatory syndrome in children (MIS-C), which typically emerges following COVID-19 infection. The rash exhibits considerable diversity and lacks specificity. However, investigations into the dermatological features of COVID-19 in children and MIS-C remain limited. Objective: To investigate cutaneous manifestations in both COVID-19 and MIS-C in children. Materials and Methods: Cross-sectional study between February and August 2022 in hospitalized children with COVID-19 who had cutaneous lesions and all hospitalized children with MIS-C. Results: Forty-six cases of COVID-19 patients with dermatological manifestations were identified among 1,602 COVID-19 patients, constituting 2.9%. Additionally, 35 cases of MIS-C were diagnosed. The majority of COVID-19 patients in the present study exhibited mild symptoms, accounting for 42 cases (91.3%). The median age of COVID-19 patients was 1.8 years, which was significantly lower than that of the MIS-C group, which was 4.3 years, with a statistically significant difference (p=0.024). The most common rash types observed in both groups were urticaria, maculopapular rash, and macular erythema. Other rash types noted in COVID-19 included erythema nodosum, Stevens-Johnson syndrome, erythema multiformelike, vesicles, and livedo reticularis. Among MIS-C patients, 31 cases (88.6%) presented with mucocutaneous manifestations, with 26 cases (74.3%) exhibiting concurrent mucocutaneous involvement. There was no significant difference in the occurrence of cardiac symptoms between the group with mucocutaneous manifestations and/or dermatological symptoms, which was 81.8%, compared to the group without mucocutaneous or dermatological symptoms, which was 100% (p=0.102). Conclusion: The cutaneous manifestations in pediatric COVID-19 and those with MIS-C vary widely and are non-specific. In patients presenting with fever and rash during a COVID-19 outbreak, recognizing these cutaneous symptoms is crucial for prompt diagnosis and treatment especially those who are asymptomatic. Further studies involving COVID-19 patients, both with and without rash, may provide correlation between disease progression and skin manifestation.

Impact of Hyponatremia and ADH Secretion in MIS-C and COVID-19: An Integrative Approach of Prognostic and Diagnostic Markers

The COVID-19 pandemic has introduced challenges in pediatric care, especially due to the emergence of Multisystem Inflammatory Syndrome in Children (MIS-C), a severe condition associated with SARS-CoV-2 infection. This study investigated the impact of hyponatremia and antidiuretic hormone (ADH) secretion corelated to clinical outcomes in these patients. We conducted a retrospective cohort study, including 118 pediatric patients, with a detailed sub-cohort analysis of 53 patients for ADH secretion markers. Hyponatremia, defined by age-specific sodium thresholds, was present in 47.22% of MIS-C cases and 28.04% of COVID-19 cases. Ordinal logistic regression analysis revealed that severe hyponatremia significantly increased the likelihood of more severe clinical outcomes (β = 3.514, p < 0.001). A significant correlation was found between hyponatremia and prolonged hospitalization. For ADH secretion, a predictive model using ridge regression was analysed, which demonstrated that serum sodium level, U/P ratio, and hospitalization duration are key predictors of SIADH. This model fit was assessed using the ROC curve with an AUC of 0.96, indicating reliable model performance. Our findings underscore the significant role of hyponatremia on the clinical severity and hospitalization outcome of COVID-19 and MIS-C in pediatric patients.

Zonulin’s Impact on Intestinal Permeability and the Development of Infant Colic: Mechanisms of Interrelation

Objective. To identify the mechanisms of the relationship between the effect of zonulin protein on the intestinal wall and the occurrence of infantile colic based on the study of scientific sources. Materials and Methods. Scientific articles were searched in PubMed, Scopus, Web of Science, and F1000Research databases. Ninety-six sources published between 1991 and 2023 were selected. Results. The history of the discovery of the zonulin protein is presented, together with a modern view of the structure of the dense intercellular junctions of the intestinal epithelium, and the processes by which the effect of zonulin on altering the permeability of the intestinal barrier is realised are described. The data of several studies in which increased levels of zonulin were found in groups of children with colic and with GI dysfunction are presented. There is a review of works in which the connection of zonulin with extraintestinal pathology - psychiatric disorders, endocrine, autoimmune, cardiopulmonary, allergic, infectious diseases - has been noted. Zonulin is a promising pharmacological target - to date, there is a specific zonulin inhibitor molecule showing efficacy in the treatment of celiac disease and multisystemic inflammatory syndrome in children. Conclusion. The analysis of publications shows the undoubted relevance of the study of zonulin as a factor affecting the permeability of the intestinal wall and a number of other processes. Its role in the formation of intestinal colic requires more detailed study, as discoveries in this area can be actively integrated into clinical practice.

Short- and medium-term longitudinal outcomes of children diagnosed with multisystem inflammatory syndrome in children - report from a single centre in Pakistan.

To determine the short- and medium-term cardiac outcomes in children admitted with multisystem inflammatory syndrome in children at a tertiary care centre in Pakistan. Children fulfilling the criteria for multisystem inflammatory syndrome and admitted to the hospital between April 2020 and March 2022 were enrolled in this prospective longitudinal cohort study. From admission to discharge, laboratory and cardiac parameters were recorded for all patients, who were subsequently followed up in clinics at various intervals. Data analysis was conducted using STATA version 15.0. A total of 51 children were included, with viral myocarditis (41.2%) and toxic shock syndrome (33.3%) being the most common phenotypes. The cardiovascular system was most commonly affected in 27 children (53%) with laboratory evidence of inflammation and myocardial injury with median and interquartile levels of ferritin 1169 (534-1704), C-reactive protein 83 (24-175), lactate dehydrogenase 468 (365-1270), N-terminal pro-B-type natriuretic peptide 8,656 (2,538-31,166), and troponin 0.16 (0.02-2.0).On admission, decreased left ventricular ejection fraction was observed in 58.8% of patients and impaired global longitudinal strain in 33.3%. At discharge, left ventricular ejection fraction had normalised in 83% of patients. Pericardial effusion resolved in all patients, and valvulitis resolved in 86% by 12 months. Paediatric ICU admission was required in 42 (82%) of patients with an overall mortality of 12% (n = 6). Our study finds high hospital mortality for multisystem inflammatory syndrome in children compared to 1-2% from previous studies. Yet, in Pakistan, surviving children with multisystem inflammatory syndrome show favourable short- to medium-term cardiac outcomes.

Characteristics of COVID-19-associated multisystemic inflammatory syndrome in children treated in a Peruvian hospital, 2020-2022.

Motivation for the study. There are few studies describing the variation of COVID-19-associated multisystem inflammatory syndrome (MIS-C) in Peru across pandemic waves. Main findings. Cases of MIS-C decreased during the first three years of the pandemic, with higher frequency in the second wave with clinical features similar to Kawasaki disease. Implications. MIS-C is a post-infectious complication of SARS-CoV-2. Its diagnostic suspicion is important weeks after peak infections, especially in children who have not yet received COVID-19 vaccines. 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.

Clinical, laboratory, and echocardiographic characteristics of critical multisystem inflammatory syndrome in children: a retrospective, observational study

ObjectiveMultisystem 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.DesignA retrospective, observational study.SettingA single-center tertiary pediatric intensive care unit (PICU).In Ain Shams university hospitals Cairo EgyptMethodsChildren 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.ResultsThe 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.ConclusionsCritical 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.

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

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

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

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

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

Abstract Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare and severe complication of SARS-CoV-2 infection that is characterized by multi-organ involvement and substantial inflammation. The immunological responses in MIS-C are not fully known. Antibody-mediated viral clearance in which innate immune cells interact with antibodies via their Fc receptors to remove the virus is an important mechanism for reducing SARS-CoV-2 viral load. However, little is known about how antibody-mediated cellular responses in MIS-C compared to acute COVID-19 infection and direct testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Therefore, we focused on the antibody-mediated cellular responses in MIS-C relative to children and adults that had acute COVID-19 infection with spectrum of symptoms. We hypothesized that cells that bind antibodies to help clear the virus are dysfunctional in MIS-C patients, preventing the virus from being fully cleared. Methods We collected samples from MIS-C children along with pediatric and adult subjects with a clinical spectrum of COVID-19 symptoms and uninfected controls. Through these controls, we can compare Fc-mediated antibody functions between ages and clinical symptoms. We utilized high dimension flow cytometry to assess phenotype and function of innate immune cells that bind to antibodies and sequencing to study Fc receptor genetic. This data was then correlated with matched clinical data. Results Monocytes in MIS-C were hyperfunctional for antibody-dependent cellular phagocytosis and production of proinflammatory cytokines. In contrast, natural killer (NK) cells in MIS-C were hypofunctional for antibody-dependent cellular cytotoxicity and cytokine production. To provide some preliminary insight into mechanism, we show multiple ways leading to decreased cytotoxicity for NK cells, including phenotypic exhaustion of NK cells, variants in CD16 (NK cell Fc receptor) genetics that reduce Fc binding to IgG, and cytokine-induced associations. Using a novel anti-CD16 novel bispecific reagent that we developed, we could rescue the hypofunctional antibody-mediated NK cell function in MIS-C to the same levels as control. Conclusion Together, our results reveal dysregulation in antibody-mediated responses that are unique to MIS-C and may contribute to the immune pathology of this disease. Specifically, we find that monocytes are hyperfunctional with NK cells are hypofunctional. In the case of the MIS-C antibody-mediated response, while it is likely that multiple pathogenetic mechanisms contribute to MIS-C, our data suggest an imbalance of the antibody-mediated cellular response as a mechanistic correlate of this rare, but life-threatening outcome of SARS-COV-2 in children. Our results highlight that targeted therapies to reduce viral burden and/or boost NK cells responses while decreasing cytokine levels may be effective in preventing MIS-C.

NK Cell and Monocyte Dysfunction in Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multiorgan involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong Ab production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 wk postinfection. Therefore, we hypothesized that dysfunctional cell-mediated Ab responses downstream of Ab production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, whereas NK cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function invitro. Taken together, our results reveal dysregulation in Ab-mediated cellular responses of myeloid and NK cells that likely contribute to the immune pathology of this disease.

Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19-PIMS-grade 3: A Case Report

Background: In the face of the rise of COVID-19, the multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 has been reported, and an increase in MIS-C cases has been observed throughout the world. The majority of these cases were similar to Kawasaki disease concerning clinical presentation. Case Presentation: Despite similarities, MIS-C cases present clinical and laboratory differentiation, which makes it essential to portray similar cases worldwide to have a better consensus in the future. A 7-year-old male child visited the hospital with the chief complaints of fever associated with chills, rigors, and excessive myalgia for 3 days. He had a history of elevated high C-reactive protein (CRP) of 42.7 mg/L. He was diagnosed with Paediatric inflammatory multisystem syndrome (PIMS)-grade 3. Here, for the first time, we bring an Indian MIS-C case with COVID-19-associated Paediatric inflammatory multisystem syndrome (PIMS)-grade 3. Conclusion: PIMS-TS infection in paediatrics is associated with a wider range of complications, and the importance of musculoskeletal complications in PIMS-TS has been discussed.

Clinical insights: Resolving the specter of cardiac sequelae in multisystem inflammatory syndrome in children (MIS-C) – A 24-month follow-up case series

Background: During the COVID-19 pandemic, multisystem inflammatory syndrome (MIS-C) emerged as a novel and severe complication. Objectives: The present prospective study followed patients in Brazil from February 2020 to December 2022, and evaluated children discharged from reference centers with an MIS-C diagnosis. The aim of the study is to describe long-term cardiac findings. Methods: Following a clinical and imaging procedure, children with MIS-C were followed up. Results: Thirty-six children during hospitalization coursed with fever; 61.1 % presented with gastrointestinal symptoms, 77.7 % with cardiocirculatory manifestations, and 28 % with respiratory issues. Shock was observed in 37 % of patients and the average hospital stay was 9 ± 5 days, with 54 % exhibiting severe symptoms requiring intensive care. Elevated inflammatory and cardiac markers were common; 42 % of patients presented elevated troponin and D-dimer levels. During intensive care, echocardiographic abnormalities were found in 56 % of the patients, including coronary dilation and pericardial effusion. All patients were hospitalized and treated with intravenous immunoglobulin, oral steroids, and acetylsalicylic acid, resulting in 86 % recovery. However, 14 % of the patient had persistent (mild cardiac) alterations at discharge. Sex and previous chronic conditions did not affect the persistence of cardiac findings, whereas marginal age differences indicated that older children tend to have more severe symptoms. BMI was identified as a risk factor but must be considered carefully. Six months post-discharge, all patients successfully recovered from cardiac alterations. Conclusion: Only few case series have reported persistent MIS-C findings, and this case series elicits a positive post-discharge prognosis for MIS-C over time.

Delirium Associated with COVID-19 in Critically ill Children: An Observational Cohort Study.

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. Retrospective, single-center cohort study. Quaternary-care pediatric intensive care unit (PICU). 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. 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. 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.