Multisystem Inflammatory Syndrome In Children Research Articles

Unraveling the complexity in diagnosis and management of multisystem inflammatory syndrome in children with kawasaki disease mimicry: a case report

Introduction and importance: COVID-19 can lead to a severe complication in children known as Multisystem Inflammatory Syndrome (MIS-C), often mimicking Kawasaki Disease (KD). This study addresses the diagnostic challenges and management of MIS-C. Case presentation: A 6-year-old female presented with fever, vomiting and rash. Clinical examination revealed cervical lymphadenopathy, periungual desquamation, lip fissures and abdominal tenderness. Echocardiography showed RCA dilatation. These findings suggested multisystem involvement and fulfilled the criteria of typical KD. The treatment was started accordingly with IVIG and empirical antibiotics. However, the confirmation of presence of SARS CoV 2 antibody led to substantial shift of diagnosis to MIS-C. Despite initial treatment, fever persisted, thus, Intravenous steroid was started which led to significant clinical improvement, rendering her almost asymptomatic in 2 weeks. Clinical discussion: Distinguishing MIS-C from KD is critical. Diagnostic criteria, epidemiology, and lab markers play a vital role. The case underscores the importance of recognizing subtle differences for accurate diagnosis and effective management. Conclusion: MIS-C, resembling KD, poses diagnostic complexities. This case emphasizes the need for clinicians to consider MIS-C in children with persistent fever and multisystem involvement post-COVID-19 exposure. Timely diagnosis and intervention are paramount for favorable outcomes in this emerging pediatric condition, urging increased awareness and reporting among healthcare professionals.

Serology supportive of recent coxsackievirus B infection is correlated with multisystem inflammatory syndrome in children (MIS-C).

Rarely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will lead to myocarditis associated with multisystem inflammatory syndrome in children (MIS-C). It remains unclear why MIS-C only targets specific children. To explore an association between coxsackievirus infections with MIS-C, we investigated the sero-epidemiology of CV in admitted pediatric patients in relation to the pandemic. This retrospective case-control study was performed by chart review of children (age ≤21 years) admitted to a tertiary care hospital with CV serological testing from January 2017 to August 2023. Clinical, laboratory, and imaging findings were used to classify patients as MIS-C and CV-unlikely or CV-possible for non-MIS-C patients. Out of 182 admissions (179 patients, median age, 6), CVB complement fixation (CF) assay on serotypes B1-B6 and CVA immunofluorescence assay IgG on serotypes A7, A9, A16, and A24 were positive in at least one serotype in 59.2% and 80.7% of cases, respectively. We observed a significant drop in CVB CF seropositivity during the peak of social distancing in 2020. The likelihood of elevated CVB CF titers was significantly higher in MIS-C than the CV-unlikely group (OR: 1.92, 95% CI: 1.02-3.63, P: 0.04) and showed a trend toward higher values in African Americans than Whites (OR: 1.57, 95% CI: 0.98-2.50, P: 0.057). The frequency of MIS-C was considerably higher in African Americans than Whites (18.1% versus 9%, P: 0.1). A higher likelihood of elevated CVB CF titers in patients with MIS-C compared with those unlikely to have acute CV infection along with a relatively higher frequency of MIS-C in African Americans warrants further investigation into the role of CVB infection in MIS-C development.IMPORTANCEThe emergence of multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic raised major concerns in providers caring for children. This condition presents a hyper-inflammation state that can lead to severe complications, including myocarditis and cardiogenic shock. The pathogenesis of MIS-C has not been fully understood. Understanding the pathogenesis of this condition is not only important for developing effective treatments but also for applying preventive strategies. A two-hit hypothesis leading to MIS-C has been proposed. Coxsackievirus infections are prevalent during childhood and can also cause myocarditis, and coxsackievirus B specifically has been shown to cause persistent RNA presence in host cells, leading to continued inflammation. Herein, we show that elevated coxsackievirus B titers are associated with MIS-C cases, implying a role of successive infections with these viruses contributing to such a hyperinflammatory state. This study supports the need for larger investigations into this association.

533 6-year-old with recurrence of multisystem inflammatory syndrome in children

533 6-year-old with recurrence of multisystem inflammatory syndrome in children

An Update on Multi-System Inflammatory Syndrome in Children.

To summarize the latest research on the epidemiology, pathogenesis, diagnosis, and treatment of multisystem inflammatory syndrome in children (MIS-C). The epidemiology of MIS-C has been dynamic since its initial description. The pathogenesis remains poorly understood. Case definitions of MIS-C have evolved over time, and practice patterns for treating MIS-C are variable with generally positive long-term outcomes yet persistent changes noted. MIS-C has become less prevalent and less severe over time, yet racial and ethnic disparities persist, and vaccination against COVID-19 is highly effective in preventing this disease. The link between acute infection and subsequent inflammation is not well understood, with growing evidence describing its immunologic signature. Newer case definitions require excluding other inflammatory conditions, including Kawasaki Disease (KD), before diagnosing MIS-C. Corticosteroid monotherapy may be non-inferior to IVIg alone or combination IVIg plus corticosteroids for initial treatment, distinguishing the approaches to MIS-C and KD. A wide range of biologic therapies have been employed for rescue therapy with general success and no clear benefit of one over another. Despite reports of a high rate of coronary artery abnormality regression and resolution of heart failure, long-term studies suggest persistent changes to cardiac function. The long-term effects of MIS-C continue to be active areas of research.

P-2004. Risk Factors for Death in Children with Multisystem Inflammatory Syndrome in Children — United States, 2020-2022

Abstract Background Although multisystem inflammatory syndrome in children (MIS-C) incidence has decreased, cases continue to occur and can have notable morbidity and mortality. This investigation evaluates clinical and demographic risk factors for death from MIS-C.Table 1.Demographic and clinical risk factors for death in children with Multisystem Inflammatory Syndrome in Children, United States, 2020-2022 Methods We evaluated children reported to CDC national MIS-C surveillance with illness onset February 2020–December 2022 and known illness outcome. We performed multivariable logistic regression to estimate odds of death compared with survival for patient characteristics and MIS-C organ involvement. Model covariates were selected a priori including age at MIS-C onset, date of MIS-C onset, race and ethnicity, and presence of any underlying medical condition. To compare risk of death across the pandemic we evaluated patients with date of MIS-C onset in five pandemic waves corresponding to peaks of MIS-C activity.Table 2.Organ system involvement risk factors for death in children with Multisystem Inflammatory Syndrome in Children, United States, 2020-2022 Results Of 8,767 MIS-C cases reported, there were 76 (9%) deaths (Table 1). Compared with children aged 5–11 years, children < 1 year and 16–20 years had increased odds of death (aOR 4.8 [1.7–13.6], p< 0.01, and 8.2 [4.6–14.8], p< 0.001, respectively). American Indian/alaska Native (AIAN) and Native Hawaiian/Pacific Islander (NHPI) children had increased odds of death compared with White non-Hispanic children (aOR 5.4 [1.4–20.9, p=0.01 and 5.9 [1.5–23.1, p=0.01, respectively). Children with MIS-C illness onset after wave 1 had decreased odds of death compared with those during wave 1. Presence of >1 underlying medical condition was associated with higher odds of death (aOR 2.3 [1.5–3.7, p< 0.001); diabetes, congenital heart disease, neurologic, immunosuppressive/autoimmune, and noncardiac congenital disorders were all independently associated with death. Cardiovascular, respiratory, neurologic, and renal MIS-C organ involvement increased odds of death while children with mucocutaneous involvement had decreased odds (Table 2). Conclusion Younger (< 1 year) and older (16-20 years) age, AIAN and NHPI race and ethnicity, MIS-C early in the pandemic, and underlying medical conditions are risk factors for death from MIS-C. Cardiovascular, respiratory, neurologic, and renal involvement increased risk of death. Identifying risk factors associated with death may help clinicians with management and prognosis. Disclosures Regina Simeone, PhD, Pfizer: Stocks/Bonds (Private Company)

P-1907. Comparing Multisystem Inflammatory Syndrome in Children (MIS-C) Case Characteristics Across Periods of SARS-CoV-2 (SC2) Variant Predominance in Los Angeles County (LAC): 2020-2023

Abstract Background MIS-C is a rare condition in children associated with prior SC2 infection. Limited data show the impact of SC2 variants on the presentation of MIS-C. This study analyzes differences in the presentation of MIS-C cases in LAC when different variants were circulating. Characteristics of Multisystem Inflammatory Syndrome in Children (MIS-C) Cases, -- Los Angeles County*, California March 1, 2020- December 31, 2023 Methods This analysis includes MIS-C cases in people < 21 years of age reported to LAC with onset from 3/1/2020-12/31/2023. We defined confirmed SC2 infection as having a documented positive SC2 test with specimen collection date < 60 days prior to MIS-C symptom onset. Where SC2 positive results were not available, we imputed SC2 infection as occurring 30 days prior to MIS-C onset. Infection dates were used to classify cases by variant predominant periods, defined as weeks where > 50% of sequenced specimens reported to LAC were a particular variant as defined by the WHO as a variant of concern. Case demographics and clinical characteristics were compared across variant periods. Analyses were conducted for all reported MIS-C cases and for cases with confirmed SC2 infection. Statistical significance was tested with the Kruskal-Wallis test and chi-squared test [α=0.05]. Results 349 MIS-C cases were reported between 2020-2023 (Table 1). Of these, 102 (29.2%) had a documented SC2 infection. Median age at onset was 7.8 years. 168 (48.1%) had ≥ 1 comorbidity, 124 (35.5%) were admitted to the ICU, and median hospital length of stay (LOS) was 5 days. 18 cases were vaccinated prior to MIS-C onset. The most SC2 infections occurred during the Pre-Delta period (230, 65.9%), while the fewest occurred during the Delta period (57, 16.3%) (Table 2). Median age and proportion of children with ≥ 1 comorbidity decreased across variant periods (p < 0.0001, p=0.0102; respectively). The median LOS was lowest when SC2 infection occurred during the Omicron period (p=0.0370). ICU admission was not statistically different across variant periods. Conclusion The LOS, median age, and proportion of cases with comorbidities decreased when SC2 infection occurred during the Omicron period. This may be due to differences in variant pathogenicity, natural immunity decreasing the MIS-C susceptible pool, and younger children being the last group to be eligible for vaccination during later variant periods. Disclosures All Authors: No reported disclosures

P-1937. Multisystem inflammatory syndrome in children (MIS-C) - Accurate Diagnosis for Targeted Treatment

Abstract Background Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory post-acute COVID-19 condition that clinically overlaps with Kawasaki disease (KD). However, the recommended first-line therapy differs for these two conditions. The Centers for Disease Control (CDC) and centers for state and territorial epidemiologists (CSTE) updated the surveillance case definition for MIS-C in 2023 to improve specificity. Since it has been suggested that 15%-20% of children identified using the 2020 definition will not meet the updated definition. While the incidence of MIS-C has decreased, waning immunity and low vaccine uptake in children requires continued vigilance and research. The objective of this study is to determine the utility of the 2023 CSTE/CDC definition to identify children with MIS-C at a quaternary care pediatric center. Methods Children diagnosed and treated for MIS-C at the Children’s of Alabama (COA) between January 2020 and December 2022 were enrolled in a prospective follow-up study. Demographic, clinical, and laboratory data, and treatment regimens were abstracted from the electronic medical record (EMR). The CDC 2020 and the 2023 CTSE/CDC criteria were applied to the cohort. Results The study cohort includes 126 children diagnosed and treated for MIS-C at COA between 2020 and 2022. The demographic and clinical features are summarized in Table 1. Of the 126 children, 92.8% (117/126) and 93.6% (118/126) respectively met the 2020 and the updated 2023 definition for MIS-C. While 81.7% (103/126) of children were treated with IVIG + steroids, 18% (23/126) were treated with IVIG only. In addition, 12 children required immunomodulators (Anakinra /Remicade /Infliximab) for resolution of symptoms after treatment with IVIG + steroids. Favorable short and mid-term outcomes were documented in all children in this cohort. Conclusion Over 90% of children with MIS-C met the criteria for MIS-C diagnosis with either the 2020 or the revised 2023 definition. The lack of definitive clinical or laboratory biomarkers and significant clinical overlap with other entities makes it challenging to identify all children with MIS-C highlighting the need for a better understanding of the pathogenesis, biomarker discovery, and effective therapies. Disclosures Swetha Pinninti, MD, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Suresh Boppana, MD, GSK: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support

P-1824. AI-Powered Differential Diagnosis: Distinguishing MIS-C from Kawasaki Disease

Abstract Background Distinguishing Multisystem Inflammatory Syndrome in Children from COVID-19 (MIS-C) from Kawasaki Disease (KD) can be challenging due to several overlapping clinical presentations. Clinical management of these conditions can vary. Hence, timely and accurate diagnosis is essential. We evaluated the potential of laboratory findings in the differentiation using machine learning (ML) models. Methods Patient demographics (Age, Sex) and laboratory data were compared between MIS-C and KD. Simultaneous CBC and routine biochemistry tests were evaluated. ML models were created using PyTorch, scikit-learn, Pandas, NumPy, and Matplotlib libraries. Specifically, Naive Bayes Classifier, KNN, Logistic Regression, SVC, Random Forest Classifier, XGBoost, GBM and LightGBM models were created and the model performances of the classifiers were evaluated with accuracy percentages. The confusion matrix of every learning model was also generated. K-fold CrossValidation was also performed to evaluate the predictive models. ROC and feature importance analysis were also performed. Identification of the disease as MIS-C or KD based on both regressive (Eg: Total Protein) and binary features (Eg: Sex) is posed as a binary classification ML problem. Train and test datasets were created using a couple of train-test splits (0.2 and 0.25). Results 209 paediatric patients with MIS-C (n=140), and KD (n=69) were included. • The accuracy performances of the models in the test set were determined as 67.8, 73.8, 75.9, 76.8, 79.9, 80.4, 81.0, 81.1%, respectively. • The area under curve (AUC) values of the LightGBM, GBM, XGBoost, were determined as 79.1, 79.5 and 78%, respectively. • Permutation importance analysis of the LightGBM model showed that elevated platelets, neutrophil count, SGPT, WBC levels, Creatinine, and NT ProBNP had influenced the model’s explainability. Conclusion Although four years have passed since the onset of COVID-19, the early diagnosis of MIS-C is still crucial. In addition to clinical findings, laboratory tests may contribute to the fight against the disease by providing early diagnosis of MIS-C and KD. Explainable ML models can help determine the appropriate markers for this purpose. Disclosures Aditya Basu, Bachelor of Technology, Triomics Healthcare: Stocks/Bonds (Private Company)

Differentiating Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Using Blood Composite Scores: Insights into Clinical Outcomes and Predictive Indices.

The study sought to assess the clinical utility of complete blood count-derived composite scores, suggesting their potential as markers of inflammation and disease severity in Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) with Kawasaki-like features. This retrospective study analyzed data from 71 KD and 73 MIS-C patients and 70 healthy controls. The KD group showed a higher rate of coronary involvement (26.7% vs. 10.9%), while the MIS-C group had a higher intensive care unit (ICU) admission rate (34.2% vs. 2.8%). Platelet counts, lymphocyte counts, mean platelet volume (MPV), MPV/Lymphocyte (MPVLR), and MPV/Platelet (MPVPR) ratios demonstrated the highest specificities in distinguishing MIS-C than KD (84.5%, 83.1%, 91.1%, 88.7%, and 88.7%, respectively). Monocyte counts, MPV, and MPVPR demonstrated the highest specificities to predictive ICU admission in the MIS-C group (83.3%, 89.6%, and 89.6%, respectively). Lymphocyte counts, platelet/lymphocyte ratio (PLR), neutrophil/lymphocyte ratio (NLR), MPVLR, and Systemic Immune-Inflammation Index (SII) parameters were found to have high negative predictive values for predicting KD patients without coronary artery lesions (CALs) (85.7%, 86.1%, 87.1%, 87.1%, and 85.7%, respectively)., Systemic Inflammation Response Index (SIRI), MPVPR, and CRP were independently predictive of ICU admission in the MIS-C group, and lymphocyte count and IVIG resistance were also identified as significant predictors of CALs in the KD group. NLR, MPVLR, MPVPR, and NPR indices effectively differentiate MIS-C from KD and predict ICU admission in MIS-C. NLR, PLR, MPVLR, and SII are valuable in excluding CALs in KD with high negative predictive values. In addition, SIRI and MPVLR were independent predictors of ICU admission in MIS-C, and lymphocyte count was identified as an independent predictor of CALs in KD.

Phenotypic Classification of Multisystem Inflammatory Syndrome in Children Using Latent Class Analysis

Multisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory illness that occurs 2 to 6 weeks after SARS-CoV-2 infection. Presentation overlaps with other conditions, and risk factors for severity differ by patient. Characterizing patterns of MIS-C presentation can guide efforts to reduce misclassification, categorize phenotypes, and identify patients at risk for severe outcomes. To characterize phenotypic clusters of MIS-C and identify clusters with increased clinical severity. In this cohort study, MIS-C phenotypic clusters were inferred using latent class analysis applied to the largest cohort to date of cases from US national surveillance data from 55 US public health jurisdictions. Cases reported to the Centers for Disease Control and Prevention MIS-C national surveillance program as of April 4, 2023, with symptom onset on or before December 31, 2022, were retrospectively analyzed. Twenty-nine clinical signs and symptoms were selected for clustering after excluding variables with 20% or more missingness and 10% or less or 90% or more prevalence. A total of 389 cases missing 10 or more variables were excluded, and multiple imputation was conducted on the remaining cases. Differences by cluster in prevalence of each clinical sign and symptom, percentage of patients admitted to the intensive care unit (ICU), length of hospital and ICU stay, mortality, and relative frequency over time. Among 8944 included MIS-C cases (median [IQR] patient age, 8.7 [5.0-12.5] years; 5407 [60.5%] male), latent class analysis identified 3 clusters characterized by (1) frequent respiratory findings primarily affecting older children (respiratory cluster; 713 cases [8.0%]; median [IQR] age, 12.7 [6.3-16.5] years), (2) frequent shock and/or cardiac complications (shock and cardiac cluster; 3359 cases [37.6%]; median [IQR] age, 10.8 [7.7-14.0] years), and (3) remaining cases (undifferentiated cluster; 4872 cases [54.5%]; median [IQR] age, 6.8 [3.6-10.3] years). The percentage of patients with MIS-C admitted to the ICU was highest for the shock and cardiac cluster (82.3% [2765/3359]) followed by the respiratory (49.5% [353/713]) and undifferentiated clusters (33.0% [1609/4872]). Among patients with data on length of stay available, 129 of 632 hospitalizations (20.4%) and 54 of 281 ICU stays (19.2%) in the respiratory cluster lasted 10 or more days compared with 708 of 3085 (22.9%) and 157 of 2052 (7.7%), respectively, in the shock and cardiac cluster and 293 of 4467 (6.6%) and 19 of 1220 (1.6%), respectively, in the undifferentiated cluster. The proportion of cases in both the respiratory cluster and the shock and cardiac cluster decreased after emergence of the Omicron variant in the US. In this cohort study, MIS-C cases clustered into 3 subgroups with distinct clinical phenotypes, severity, and distribution over time. Use of clusters in future studies may support efforts to evaluate surveillance case definitions and identify groups at highest risk for severe outcomes.

Serum HDL and their subfractions are impaired in multisystem inflammatory syndrome in children (MIS-C)

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a severe post-COVID condition due to a delayed hyperimmune response to SARS-CoV-2. High-density lipoproteins (HDL) are pivotal players in inflammatory and immune modulation through the remodeling of their subfractions.MethodsThis study aimed to evaluate serum levels of cholesterol, HDL, and HDL subfractions (HDL-SUB) to define their role in the pathogenesis of MIS-C and their potential use as biomarkers of this condition. We analyzed serum cholesterol, HDL and HDL-SUB (by capillary electrophoresis) in relation to serum values of biomarkers of inflammation and endothelial damage (by microfluidic immunoassays) in 48 patients with MIS-C at hospital admission and in 48 age- and sex-matched healthy controls.ResultsSerum cholesterol, as well as HDL, were significantly lower in MIS-C patients than controls. Serum cholesterol was inversely correlated with all biomarkers of inflammation, confirming the impact of cytokines on reverse cholesterol transport, whereas HDL values were inversely correlated with serum biomarkers of endothelial damage, suggesting a role of HDL in endothelial damage in MIS-C patients. Furthermore, we found a remodeling of HDL-SUB with a more pronounced decrease in small HDL that have anti-inflammatory activity.ConclusionsThese data confirm the severe impairment of reverse cholesterol transport in MIS-C and indicate serum HDL and HDL-SUB as potential useful diagnostic biomarkers of MIS-C.

Six-Month Outcomes in the Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children Study

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication of COVID-19 infection. Data on midterm outcomes are limited. To characterize the frequency and time course of cardiac dysfunction (left ventricular ejection fraction [LVEF] <55%), coronary artery aneurysms (z score ≥2.5), and noncardiac involvement through 6 months after MIS-C. This cohort study enrolled participants between March 2020 and January 2022 with a follow-up period of 2 years. Participants were recruited from 32 North American pediatric hospitals, and all participants met the 2020 Centers for Disease Control and Prevention case definition of MIS-C. MIS-C after COVID-19 infection. Outcomes included echocardiography core laboratory (ECL) assessments of LVEF and maximum coronary artery z scores (zMax); data collection on cardiac and noncardiac sequelae during hospitalization and at 2 weeks, 6 weeks, and 6 months after discharge; and age-appropriate Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health Instruments at follow-up. Descriptive statistics, linear regression models, and Kaplan-Meier analysis were used. Of 1204 participants (median [IQR] age, 9.1 [5.6-12.7] years; 724 male [60.1%]), 325 self-identified with non-Hispanic Black race (27.0%) and 324 with Hispanic ethnicity (26.9%). A total of 548 of 1195 participants (45.9%) required vasoactive support, 17 of 1195 (1.4%) required extracorporeal membrane oxygenation, and 3 (0.3%) died during hospitalization. Of participants with echocardiograms reviewed by the ECL (n = 349 due to budget constraints), 131 of 322 (42.3%) had LVEF less than 55% during hospitalization; of those with follow-up, all but 1 normalized by 6 months. Black race (vs other/unknown race), higher C-reactive protein level, and abnormal troponin level were associated with lowest LVEF (estimate [SE], -3.09 [0.98]; R2 = 0.14; P =.002). Fifteen participants had coronary artery z scores of 2.5 or greater at any time point; 1 participant had a large/giant aneurysm. Of the 13 participants with z scores of 2.5 or greater during hospitalization, 12 (92.3%) had normalized by 6 months. Return to greater than 90% of pre-MIS-C health status (energy, sleep, appetite, cognition, and mood) was reported by 711 of 824 participants (86.3%) at 2 weeks, increasing to 548 of 576 (95.1%) at 6 months. Fatigue was the most common symptom reported at 2 weeks (141 of 889 [15.9%]), falling to 3.4% (22 of 638) by 6 months. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months (fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3; P < .001) and by the 6-week visit were at least equivalent to prepandemic population norms. Results of this cohort study suggest that although children and young adults with MIS-C can have severe disease during the acute phase, most recovered quickly and had a reassuring midterm prognosis.

Off-Label Use of Anakinra in Inflammatory Conditions in Neonates and Infants Up to 3 Months of Age: A Case Series and a Review of the Literature.

Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Since IL-1 has been shown to play a key role in the etiology of different autoinflammatory diseases, blocking its pathway has become an important therapeutic target, even in neonates. We aimed to report our experience in using anakinra to treat specific neonatal inflammatory conditions. We described the clinical management with anakinra of five cases of neonates or infants up to 3 months of age admitted to the neonatal intensive care unit (NICU) of Bambino Gesù Children's Hospital IRCCS in Rome (Italy) from 2020 onwards. Medical history and clinical data concerning NICU hospitalization were collected from the electronic medical records. Furthermore, we performed a literature review of off-label anakinra in the first 3 months of life, up to 5 April 2024. We excluded from this review cases of cryopyrin-associated periodic syndrome, deficiency of the interleukin-1 receptor antagonist, and mevalonate kinase deficiency, for which anakinra is a known treatment. We reported three off-label cardiorespiratory reasons to use IL-1Ra from our series: (i) chronic lung disease with pulmonary hypertension, (ii) interstitial lung disease with pulmonary hypertension to facilitate the weaning from respiratory support, and (iii) post-surgical polyserositis if effusions accumulate despite drainage. In all our patients, the drug was administered at a dosage of 10mg/kg/day. The route of administration was chosen based on the patient's clinical characteristics, with the subcutaneous and intravenous routes being comparable in efficacy. The duration of therapy was modulated based on the patient's clinical response, with a minimum duration of 4 months. A total of 308 retrieved articles were screened, and then full texts of records deemed eligible for inclusion were assessed. Based on the literature search and our five cases, a total of 17 infants were treated with anakinra outside its approved indications. The major off-label use was for hemophagocytic lymphohistiocytosis/macrophage activation syndrome, followed by multisystem inflammatory syndrome in children and Kawasaki disease, as in two of our cases. According to the results of our case series and review of the literature, the off-label use of anakinra in neonates with inflammatory conditions refractory to first-line therapy could be considered. Prospective, multicenter research is necessary to determine whether anakinra is a safe treatment option for these infants to prevent early inflammatory illnesses and in which situations it could enhance clinical results.

Distinguishing Multisystem Inflammatory Syndrome in Children From Typhus Using Artificial Intelligence: MIS-C Versus Endemic Typhus (AI-MET)

Abstract Background The pandemic emergent disease multisystem inflammatory syndrome in children (MIS-C) following coronavirus disease-19 infection can mimic endemic typhus. We aimed to use artificial intelligence (AI) to develop a clinical decision support system that accurately distinguishes MIS-C versus endemic typhus (MET). Methods Demographic, clinical, and laboratory features rapidly available following presentation were extracted for 133 patients with MIS-C and 87 patients hospitalized due to typhus. An attention module assigned importance to inputs used to create the 2-phase AI-MET. Phase 1 uses 17 features to arrive at a classification manually (MET-17). If the confidence level is not surpassed, 13 additional features are added to calculate MET-30 using a recurrent neural network. Results While 24 of 30 features differed statistically, the values overlapped sufficiently that the features were clinically irrelevant distinguishers as individual parameters. However, AI-MET successfully classified typhus and MIS-C with 100% accuracy. A validation cohort of 111 additional patients with MIS-C was classified with 99% accuracy. Conclusions Artificial intelligence can successfully distinguish MIS-C from typhus using rapidly available features. This decision support system will be a valuable tool for front-line providers facing the difficulty of diagnosing a febrile child in endemic areas.

Multisystem Inflammatory Syndrome in Children—Emerging Insights From Large Datasets

Multisystem Inflammatory Syndrome in Children—Emerging Insights From Large Datasets

Multidimensional 1-Year Outcomes After Intensive Care Admission for Multisystem Inflammatory Syndrome in Children.

The COVID-19 pandemic gave rise to uncertainty concerning potential sequelae related to a severe acute respiratory syndrome coronavirus 2 infection. This landscape is currently unfolding with studies reporting sequelae on various domains (physical, cognitive, and psychosocial), although most studies focus on adults or only one domain. We sought to investigate concurrent sequelae on multiple domains 1 year after PICU admission for Multisystem Inflammatory Syndrome in Children (MIS-C). Prospective cohort study. Two academic, tertiary referral hospitals in The Netherlands and Belgium. Patients (< 18 yr, n = 58) seen in-person 1-year after PICU admission for MIS-C. None. Seventy MIS-C patients (62% male; median age, 10.0 [interquartile range, 7.4-13.0]) were admitted to the PICU, mostly (86%) due to (imminent) circulatory failure. The majority received IV immunoglobulins (95%), steroids (83%), and vasopressors and/or inotropes (72%). Invasive respiratory support and extracorporeal membrane oxygenation were necessary in 7% and 2%, respectively. All patients survived. Fifty-eight patients (83%) attended 1-year follow-up. Although most patients had normal functional performance scores (Pediatric Cerebral Performance Category, Pediatric Overall Performance Category, and Functional Status Score), 62% still experienced physical sequelae: fatigue (40%), headaches (27%), and decreased exercise tolerance (19%). Cognitive, behavioral, and psychological problems were reported in 14%, 13%, and 23%, respectively. This resulted in 22% requiring ongoing healthcare utilization, 9% not being able to return to full-time school attendance and cessation of hobbies in 7%. This is the first 1-year outcome study of MIS-C PICU patients to include both physical and psychosocial characteristics. One year after PICU admission, most children had normalized functional performance as measured by three validated performance scores. However, many still reported a variety of multidimensional sequelae at 1-year follow-up impacting daily life. This emphasizes the importance of continued investigative efforts and multidisciplinary follow-up programs to better understand pathophysiology and contributing factors to the MIS-C disease trajectory and initiate patient-specific interventions to improve outcome and social participation.

Risk of Kawasaki Disease/Multisystem Inflammatory Syndrome Following COVID-19 Vaccination in Korean Children: A Self-Controlled Case Series Study.

Rare cases of Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) have been reported following the coronavirus disease 2019 (COVID-19) vaccination; however, the association between COVID-19 vaccination and the risk of developing KD/MIS-C has not yet been established. We conducted a self-controlled case series analysis using a large-linked database that connects the COVID-19 immunization registry with nationwide claims data. We identified individuals aged < 18 years who received their initial COVID-19 vaccination and had a KD/MIS-C diagnosis with a prescription for intravenous immunoglobulin or corticosteroids between October 18, 2021, and April 15, 2023. The observation period was set as 240 days from the date of the COVID-19 vaccination. The risk window was 60 days after vaccination, with the remaining observation period serving as the control window. The incidence rate ratios (IRRs) and 95% confidence intervals (CIs) in the risk versus control windows were estimated using the conditional Poisson regression model. We further analyzed the vaccine doses and types for secondary analysis. We also performed subgroup analyses stratified by sex, age, comorbidities, and other conditions and sensitivity analyses by varying the length of the risk window and outcome definition. Among 2,369,490 individuals who received the COVID-19 vaccination, 12 cases of KD/MIS-C were identified, which included five and seven patients in the risk and control windows, respectively. There was no increased risk of KD/MIS-C within the 60-day period of vaccination (IRR, 0.53; 95% CI, 0.17-1.60). Secondary subgroup and sensitivity analyses showed no significant increase in the risk of KD/MIS-C after COVID-19 vaccination, which is consistent with the results of the main analysis. The results of this nationwide study suggest that the risk of developing KD/MIS-C did not increase after COVID-19 vaccination. However, owing to the lack of a sufficient number of cases, future studies utilizing multinational long-term follow-up databases should be conducted. Considering the increasing incidence of KD/MIS-C and the limited understanding of its precise biological mechanisms, additional research on KD/MIS-C is warranted.

COVID-19 vaccine effectiveness against severe omicron-related outcomes in children aged 5 to 11 years in Ontario: A Canadian immunization research network (CIRN) study

BackgroundUnderstanding how the efficacy of COVID-19 vaccines translates from clinical trials to real-world settings is critical to inform evolving vaccination policies. The objective of this study was to assess COVID-19 vaccine effectiveness (VE) against severe COVID-19-related outcomes in children aged 5–11 years, including COVID-19-related hospital admissions and multisystem inflammatory syndrome in children (MIS-C). MethodsWe conducted a retrospective, population-based cohort study using linked health administrative data in the first year following the emergence of the Omicron variant (January 2 to December 31, 2022) in Ontario, Canada. Baseline differences between subgroups of interest were compared using standardized differences. We used multivariable Cox proportional hazard regression models to estimate VE by time since last vaccine dose by treating vaccination as a time-varying exposure, compared to unvaccinated children. ResultsWe included a total of 1,058,740 children, of which 583,867 (55.1 %) had received at least one vaccine dose by the end of the study period. In total, there were 185 COVID-19-related hospital admissions and 39 cases of MIS-C. The rate of COVID-19-related admission was substantially higher in children with an underlying comorbid condition compared to children who were previously healthy (adjusted hazard ratio [aHR] = 4.77, 95 %CI, 3.56–6.38). VE against COVID-19-related admission ranged from 93 % (95 %CI, 52–99 %) 7–29 days after a second dose to 63 % (95 %CI; 41–77 %) ≥120 days after a second dose. There was no statistically significant difference in the rate of MIS-C in children who received at least one dose of the vaccine compared to unvaccinated children (aHR = 0.71; 95 %CI, 0.38–1.34). ConclusionsWe found that, for children aged 5–11 years, VE against COVID-19-related hospitalization was high in the first four months after a second dose. Children with comorbid conditions were found to be at much higher risk of COVID-19-related severe outcomes and thus may benefit most from COVID-19 vaccination.

Multisystem inflammatory syndrome in children (MIS-C): Clinical presentation and management of critically ill cases

Multisystem inflammatory syndrome in children (MIS-C): Clinical presentation and management of critically ill cases

Assessing the Role of Environmental Health in Infectious Disease Control

Introduction: Environmental health, infectious disease control, environmental determinants of disease transmission, ecological exposures, COVID-19, air pollution, contagious diseases, and multisystem inflammatory syndrome in children (MIS-C)..Methods: The researcher used a mixed-methods approach, conducting both quantitative analyses of epidemiological data and qualitative interviews with public health experts. Multiple geographic locations with different environmental conditions were used to ascertain disease incidence. The study reviewed the existing literature to inventory and classify existing ecological health interventions..Results: The results showed a substantial association between better environmental health interventions and lower prevalence of communicable diseases. In regions with improved sanitation, access to clean water, and waste management, case studies confirmed a significant reduction in disease outbreaks. Interviews with experts emphasized that environmental health approaches can be integrated into existing public health efforts, such as those aimed at controlling vectors and reducing pollution..Conclusions: We show that enhanced environmental health systems were foundational to the control of infectious diseases [34]. Public health outcomes significantly improved through a recognition of ecological determinants and the application of targeted interventions. The study highlighted the need for policymakers to embrace environmental health in disease prevention approaches, suggesting more significant investment and intersect oral action to create sustained impacts.