Multisystem Inflammatory Syndrome In Children Patients Research Articles

The plasma proteome differentiates the multisystem inflammatory syndrome in children (MIS-C) from children with SARS-CoV-2 negative sepsis

BackgroundThe Multi-System Inflammatory Syndrome in Children (MIS-C) can develop several weeks after SARS-CoV-2 infection and requires a distinct treatment protocol. Distinguishing MIS-C from SARS-CoV-2 negative sepsis (SCNS) patients is important to quickly institute the correct therapies. We performed targeted proteomics and machine learning analysis to identify novel plasma proteins of MIS-C for early disease recognition.MethodsA case-control study comparing the expression of 2,870 unique blood proteins in MIS-C versus SCNS patients, measured using proximity extension assays. The 2,870 proteins were reduced in number with either feature selection alone or with a prior COMBAT-Seq batch effect adjustment. The leading proteins were correlated with demographic and clinical variables. Organ system and cell type expression patterns were analyzed with Natural Language Processing (NLP).ResultsThe cohorts were well-balanced for age and sex. Of the 2,870 unique blood proteins, 58 proteins were identified with feature selection (FDR-adjusted P < 0.005, P < 0.0001; accuracy = 0.96, AUC = 1.00, F1 = 0.95), and 15 proteins were identified with a COMBAT-Seq batch effect adjusted feature selection (FDR-adjusted P < 0.05, P < 0.0001; accuracy = 0.92, AUC = 1.00, F1 = 0.89). All of the latter 15 proteins were present in the former 58-protein model. Several proteins were correlated with illness severity scores, length of stay, and interventions (LTA4H, PTN, PPBP, and EGF; P < 0.001). NLP analysis highlighted the multi-system nature of MIS-C, with the 58-protein set expressed in all organ systems; the highest levels of expression were found in the digestive system. The cell types most involved included leukocytes not yet determined, lymphocytes, macrophages, and platelets.ConclusionsThe plasma proteome of MIS-C patients was distinct from that of SCNS. The key proteins demonstrated expression in all organ systems and most cell types. The unique proteomic signature identified in MIS-C patients could aid future diagnostic and therapeutic advancements, as well as predict hospital length of stays, interventions, and mortality risks.

Differentiating Multisystem Inflammatory Syndrome in Children from Kawasaki Disease During the Pandemic.

We aimed to delineate the distinctive characteristics that aid in distinguishing between Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) with KD-like manifestations during the pandemic. We evaluated KD patients and MIS-C patients with KD-like symptoms admitted during the pandemic (between January 2021 and December 2022). Thirty-three MIS-C patients and 15 KD patients were included. Kawasaki disease patients were younger than MIS-C patients (3.4 vs. 7.6 years). Rash (P = .044, 100% vs. 75.7%), oral mucosal changes (P = .044, 100% vs. 75.7%), and cervical lymphadenopathy (P = .001, 93.3% vs. 42.4%) were more common in KD. Multisystem inflammatory syndrome in children: patients had more hypotension (P = .002, 45.4% vs. 0), gastrointestinal (P .001, 72.7% vs. 13.3%), and respiratory symptoms (P = .044, 24.2% vs. 0). Multisystem inflammatory syndrome in children patients also had low lymphocyte and thrombocyte counts and elevated levels of d-dimer, ferritin, and cardiac parameters, unlike KD patients. Multisystem inflammatory syndrome in children patients exhibited a notable reduction in left ventricular systolic function in echocardiography. Another significant difference with regard to management was the anakinra treatment, which was prescribed for MIS-C patients. Although MIS-C patients might display a clinical resemblance to KD, several features could help differentiate between MIS-C and classical KD. Specific clinical (hypotension, gastrointestinal, and respiratory symptoms) and laboratory (low lymphocyte and thrombocyte counts with higher C-reactive protein, ferritin, d-dimer, and cardiac parameters) features are characteristic of MIS-C. In addition, divergence in management strategies is evident between the 2 diseases, as biologic drugs were more prevalently employed in MIS-C patients than in classical KD patients.

Longitudinal Cardiac Evaluation of Children with Multisystem Inflammatory Syndrome (MIS-C) Following COVID-19 by Conventional and Speckle-Tracking Echocardiography

Multisystem inflammatory syndrome in children (MIS-C), is a rare but severe, hyperinflammatory complication of COVID-19, in which cardiovascular abnormalities are frequently detected. In this prospective study, we describe the echocardiographic findings in patients with MIS-C, with the use of conventional Echocardiography and Speckle-Tracking Echocardiography (STE) with Left Ventricular (LV) Global Longitudinal Strain (GLS) analysis, in the acute and follow-up phase. In total, 25 MIS-C patients [64% females, mean (± SD) age: 8.3 (± 3.72) years] were included. In the acute phase, median (IQR) Troponin and NT-proBNP and mean heart rate, were 8.07 (14.52) pg/mL, 2875.00 (7713.00) pg/mL, and 102.87 (± 22.96) bpm, respectively. Median (IQR) LV Ejection Fraction (LVEF) was 66 (8)% and LVEF impairment was detected in 2/25 (8%) patients. On follow-up (mean time interval:9.50 ± 4.59 months), heart rate was significantly lower, with a mean value of 90.00 (± 14.56) bpm (p-value = 0.017). Median (IQR) LVEF was 66.00 (6.70)% (p-value = 0.345) and all 25 participants had normal LVEF. In 14/25 patients, additional LV-GLS analysis was performed. During the acute phase, mean LV-GLS was − 18.02 (± 4.40)%. LV-GLS was abnormal in 6/14 patients (42.9%) and among them, only one patient had reduced LVEF. On follow-up (median (IQR) time interval:6.93 (3.66) months), mean LV-GLS was -20.31 (± 1.91)% (p-value = 0.07) and in 1/14 patient (7.1%), the LV-GLS impairment persisted. In conclusion, in the acute and follow-up phase, we detected abnormal LV-GLS values in some patients, in the presence of normal LVEF, indicating that STE-GLS is a valuable tool for identifying subclinical myocardial injury in MIS-C.

Left Atrial Strain in Multisystem Inflammatory Syndrome in Children and Associations with Systemic Inflammation and Cardiac Injury.

Multisystem inflammatory syndrome in children (MIS-C) commonly involves cardiac injury with both systolic and diastolic dysfunction. Left atrial strain (LAS) detects subclinical diastolic dysfunction in adults but is infrequently used in children. We evaluated LAS in MIS-C and the associations with systemic inflammation and cardiac injury. In this retrospective cohort study, LAS parameters [reservoir (LAS-r), conduit (LAS-cd), and contractile (LAS-ct)] obtained from admission echocardiograms of MIS-C patients were compared to healthy controls and between MIS-C patients with and without cardiac injury (BNP > 500pg/ml or troponin-I > 0.04ng/ml). Correlation and logistic regression analyses were performed to assess LAS associations with admission inflammatory and cardiac biomarkers. Reliability testing was performed. We identified 118 patients with MIS-C and 20 healthy controls. Median LAS parameters were reduced in MIS-C patients compared to controls (LAS-r: 31.8 vs. 43.1%, p < 0.001; LAS-cd: -28.8 vs. -34.5%, p = 0.006; LAS-ct: -5.2 vs. -9.3%, p < 0.001) and reduced in MIS-C patients with cardiac injury (n = 59) compared to no injury (n = 59) (LAS-r: 29.6 vs. 35.8%, p = 0.001; LAS-cd: -26.5 vs. -30.4%, p = 0.036; LAS-ct: -4.6 vs. -9.3%, p = 0.008). A discrete LAS-ct peak was absent in 65 (55%) MIS-C patients but present in all controls (p < 0.001). Procalcitonin correlated strongly with averaged E/e' (r = 0.55, p = 0.001). Moderate correlations were found for ESR and LAS-ct (r = -0.41, p = 0.007) as well as BNP and LAS-r (r = -0.39, p < 0.001) and LAS-ct (r = 0.31, p = 0.023). Troponin-I had only weak correlations. Intra-rater reliability was good for all LAS parameters, and inter-rater reliability was good to excellent for LAS-r, and fair for LAS-cd and LAS-ct. LAS analysis, particularly the absence of a LAS-ct peak, was reproducible and may be superior to conventional echocardiographic parameters for detecting diastolic dysfunction in MIS-C. No strain parameters on admission were independently associated with cardiac injury.

Emergency myelopoiesis distinguishes multisystem inflammatory syndrome in children from pediatric severe COVID-19.

Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent SARS-CoV-2 infection, but the underlying immunological mechanisms driving this distinct syndrome are unknown. We utilized high dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute COVID-19 (SAC). Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen presenting cells. IL-27, a cytokine known to drive hematopoietic stem cells towards EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased, and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood. Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing towards MIS-C, offering potential diagnostic and therapeutic targets.

Cardiac Biomarkers Aid in Differentiation of Kawasaki Disease from Multisystem Inflammatory Syndrome in Children Associated with COVID-19.

Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show clinical overlap and both lack definitive diagnostic testing, making differentiation challenging. We sought to determine how cardiac biomarkers might differentiate KD from MIS-C. The International Kawasaki Disease Registry enrolled contemporaneous KD and MIS-C pediatric patients from 42 sites from January 2020 through June 2022. The study population included 118 KD patients who met American Heart Association KD criteria and compared them to 946 MIS-C patients who met 2020 Centers for Disease Control and Prevention case definition. All included patients had at least one measurement of amino-terminal prohormone brain natriuretic peptide (NTproBNP) or cardiac troponin I (TnI), and echocardiography. Regression analyses were used to determine associations between cardiac biomarker levels, diagnosis, and cardiac involvement. Higher NTproBNP (≥ 1500ng/L) and TnI (≥ 20ng/L) at presentation were associated with MIS-C versus KD with specificity of 77 and 89%, respectively. Higher biomarker levels were associated with shock and intensive care unit admission; higher NTproBNP was associated with longer hospital length of stay. Lower left ventricular ejection fraction, more pronounced for MIS-C, was also associated with higher biomarker levels. Coronary artery involvement was not associated with either biomarker. Higher NTproBNP and TnI levels are suggestive of MIS-C versus KD and may be clinically useful in their differentiation. Consideration might be given to their inclusion in the routine evaluation of both conditions.

Abstract 15474: Factors Associated With Shock at Presentation for Patients With Kawasaki Disease versus Multisystem Inflammatory Syndrome in Children Associated With COVID-19

Background: Comparisons between Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) have been critiqued, with suggestions that KD Shock Syndrome (KDSS) patients may be a more valid comparison. We compared contemporaneous KD and MIS-C patients, both with and without shock at presentation. Methods: The International KD Registry enrolled 2144 patients with either KD (site diagnosis confirmed by AHA criteria) or MIS-C (site diagnosis confirmed by CDC criteria) from 40 sites in 7 countries from 01/2020 to 01/2023. Data collected included demographics, clinical features and presentation, management, laboratory values, and outcomes, and diagnosis/shock groups were compared. Results: Shock at presentation was noted for 19 of 672 (2.8%) KD patients and 653 of 1472 (38%; p&lt;0.001) MIS-C patients. For both groups, shock patients were significantly more likely to be admitted to ICU, receive inotropes, and have cardiac arrest or arrhythmia. Groups did not differ by sex, but MIS-C patients and shock patients were older. While MIS-C shock patients were less likely to be White, KD shock and MIS-C shock patients more likely to be Black. For inflammatory markers, while shock patients in both groups had higher CRP and ferritin compared to non-shock patients, ESR was similar in both groups to non-shock patients, and higher WBC was only noted for MIS-C shock versus MIS-C non-shock patients. KD shock patients had similar values to MIS-C shock patients, with the exception of lower ferritin. Shock patients had higher NTproBNP (both diagnoses) and Troponin I (MIS-C only). Shock patients had lower LV ejection fraction, more so for MIS-C patients ( Figure A ). KD shock patients had higher max coronary artery Z scores versus MIS-C patients ( Figure B ). Conclusions: KD shock patients are more similar to MIS-C patients, particularly those with shock. Shock was associated with worse coronary artery involvement for KD patients, and worse LV dysfunction for both MIS-C and KD.

Abstract 13839: Value of 2D Speckle Tracking Echocardiography in Predicting Short-Term Cardiovascular Outcomes in Multisystem Inflammatory Syndrome in Children: Analysis of the MUSIC Data

Introduction: Cardiovascular (CV) involvement in multisystem inflammatory syndrome in children (MISC) is frequent (80-85%). Data on 2D speckle tracking echocardiography and its value in predicting CV outcomes are limited. Hypothesis: We hypothesized that an association exists between 2D speckle tracking strain/strain rate parameters at admission and adverse CV outcomes during hospitalization (inotropic support, major arrhythmias, cardiac arrest, ECMO, death, or transplant). Methods: We performed a multicenter (33 centers) cohort study on MISC patients hospitalized from 03/2020 to 11/2021 with at least one echocardiogram read by the Core Lab. The association between each 2D speckle tracking strain parameter and adverse CV outcomes was assessed by logistic regression. Results: Of 349 patients (median age 8.7 years [IQR 5.3,12.9]), 122 (35%) had decreased left ventricle (LV) ejection fraction (EF) and 156 (45%) had depressed LV 4-chamber longitudinal strain (LS) or basal circumferential strain (CS) during hospitalization. Worst EF and strain occurred around 5 days of illness. Of those with abnormal LS or CS strain, 50% normalized in ≤1 week, 95% within 50 days. Adverse CV outcomes occurred in 121 (35%) patients. Patients with adverse outcomes were older (p=0.003), more likely to have an underlying metabolic/genetic disorder (p=0.015), abnormal troponin (p&lt;0.001), and higher C-reactive protein (CPR) at admission (p&lt;0.001). They also had higher indexed LV end-diastolic volume (p&lt;0.001) and mass (p=0.015), worse EF (p&lt;0.001), worse LS (p=0.002), and worse CS (p=0.001). When adjusting for days of illness, age, gender, race, obesity, comorbidities, SARS-CoV-2 positivity, CRP, and abnormal troponin at admission, LS Z-score (adjusted OR 1.24 [95% CI 1.03,1.49], AUC 0.754 and longitudinal early diastolic strain rate (LEDSR; adjusted OR 1.98 [IQR 1.18, 3.33], AUC 0.760) at admission were independently associated with adverse CV outcomes. Conclusion: Almost half of the MISC patients had abnormal LS or CS at admission, but the majority recovered quickly. LS and LEDSR at admission were independently associated with adverse CV outcomes. These data may help in early characterization, risk stratification, and prognostication in patients with MISC.

Abstract 15506: Pattern of Use of Anakinra for Patients With Kawasaki Disease versus Multisystem Inflammatory Syndrome in Children Associated With COVID-19

Background/Aims: Anakinra (interleukin-1 blocker) has emerged as a potential adjunctive therapy for treating resistant acute Kawasaki disease (KD) and those with evolving aneurysms, and has been used as both primary and adjunct therapy for treating Multisystem Inflammatory Syndrome in Children (MIS-C), both in the absence of randomized trials. We sought to determine patterns of use, adverse events and evidence of benefit. Methods: The International KD Registry contemporaneously enrolled 727 patients with KD (site diagnosis confirmed by AHA criteria) and 1476 with MIS-C (site diagnosis confirmed by CDC criteria) from 39 sites in 7 countries from 01/2020 to 01/2023. Data collected included demographics, clinical features and presentation, management, laboratory values, and outcomes. Results: Anakinra was used at 22 (56%) sites for 11 (1.5%) KD patients (median duration 21 days) and 257 (17.4%) MIS-C patients (8 days; 11% discharged on anakinra). For KD, anakinra was used for treatment resistance for 5 sites, evolving aneurysms 3, macrophage activation syndrome (MAS) 1 and not-specified for 2. For MIS-C, anakinra use was determined by protocol for 3 sites, on a case-by-case basis for 10, reserved for treatment failure for 3 and not-specified for 6 sites. Reported indications for use (may be multiple) included routine use for ICU patients for 34% of treated MIS-C patients, worsening/persistent lab abnormalities 28%, critical decompensation (primarily cardiac) 21%, persistent/recurrent fever 21%, treatment failure 9%, coronary artery abnormalities 8%, and cytokine storm/MAS for 4%. Adverse events in treated MIS-C patients were noted for 23 (9%) and included neutropenia in 9, transaminitis 8, injection site pain/rash 4 and one each with anemia and thrombocytopenia. Extreme patient heterogeneity and confounding by indication precluded a formal analysis of impact on outcomes, although sites reported evidence of clinical improvement relevant to reported indications for all but one patient. Conclusions: Greater anakinra use for MIS-C vs KD likely reflects greater perceived indication, primarily greater clinical and inflammatory severity. Subjective evidence of benefit and a low prevalence of adverse events suggest an ongoing role for anakinra.

Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomic analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared to pediatric healthy controls (pHC) and pCOVID-19, MIS-C patients had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and non-hematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Non-hematopoietic tissue cfDNA levels demonstrated significant inter-individual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the innate immune cells cfDNA in MIS-C correlated with levels of innate immune inflammatory cytokines and non-hematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for multi-system pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multi-organ inflammatory conditions.

Preliminary Evidence of the Differential Expression of Human Endogenous Retroviruses in Kawasaki Disease and SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some clinical features overlapping with Kawasaki disease (KD). Our research group and others have highlighted that the spike protein of SARS-CoV-2 can trigger the activation of human endogenous retroviruses (HERVs), which in turn induces inflammatory and immune reactions, suggesting HERVs as contributing factors in COVID-19 immunopathology. With the aim to identify new factors involved in the processes underlying KD and MIS-C, we analysed the transcriptional levels of HERVs, HERV-related genes, and immune mediators in children during the acute and subacute phases compared with COVID-19 paediatric patients and healthy controls. The results showed higher levels of HERV-W, HERV-K, Syn-1, and ASCT-1/2 in KD, MIS-C, and COV patients, while higher levels of Syn-2 and MFSD2A were found only in MIS-C patients. Moreover, KD and MIS-C shared the dysregulation of several inflammatory and regulatory cytokines. Interestingly, in MIS-C patients, negative correlations have been found between HERV-W and IL-10 and between Syn-2 and IL-10, while positive correlations have been found between HERV-K and IL-10. In addition, HERV-W expression positively correlated with the C-reactive protein. This pilot study supports the role of HERVs in inflammatory diseases, suggesting their interplay with the immune system in this setting. The elevated expression of Syn-2 and MFSD2A seems to be a distinctive trait of MIS-C patients, allowing to distinguish them from KD ones. The understanding of pathological mechanisms can lead to the best available treatment for these two diseases, limiting complications and serious outcomes.

Renal Involvement in Multisystem Inflammatory Syndrome in Children: Not Only Acute Kidney Injury.

Kidney involvement has been poorly investigated in SARS-CoV-2 Multisystem Inflammatory Syndrome in Children (MIS-C). To analyze the spectrum of renal involvement in MIS-C, we performed a single-center retrospective observational study including all MIS-C patients diagnosed at our Pediatric Department between April 2020 and May 2022. Demographic, clinical, pediatric intensive care unit (PICU) admission's need and laboratory data were collected at onset and after 6 months. Among 55 MIS-C patients enrolled in the study, kidney involvement was present in 20 (36.4%): 13 with acute kidney injury (AKI) and 7 with isolated tubular dysfunction (TD). In eight patients, concomitant AKI and TD was present (AKI-TD). AKI patients needed higher levels of intensive care (PICU: 61.5%, p < 0.001; inotropes: 46.2%, p = 0.002; second-line immuno-therapy: 53.8%, p < 0.001) and showed lower levels of HCO3- (p = 0.012), higher inflammatory markers [neutrophils (p = 0.092), PCT (p = 0.04), IL-6 (p = 0.007)] as compared to no-AKI. TD markers showed that isolated TD presented higher levels of HCO3- and lower inflammatory markers than AKI-TD. Our results indicate a combination of both pre-renal and inflammatory damage in the pathogenesis of kidney injury in MIS-C syndrome. We highlight, for the first time, the presence of tubular involvement in MIS-C, providing new insights in the evaluation of kidney involvement and its management in this condition.

Epidemiology and Severity of Illness of MIS-C and Kawasaki Disease During the COVID-19 Pandemic.

Multisystem inflammatory syndrome in children (MIS-C) is a novel, severe condition following severe acute respiratory syndrome coronavirus 2 infection. Large epidemiologic studies comparing MIS-C to Kawasaki disease (KD) and evaluating the evolving epidemiology of MIS-C over time are lacking. We sought to understand the illness severity of MIS-C compared with KD and evaluate changes in MIS-C illness severity over time during the coronavirus disease 2019 pandemic compared with KD. We included hospitalizations of children with MIS-C and KD from April 2020 to May 2022 from the Pediatric Health Information System administrative database. Our primary outcome measure was the presence of shock, defined as the use of vasoactive/inotropic cardiac support or extracorporeal membrane oxygenation. We examined the volume of MIS-C and KD hospitalizations and the proportion of hospitalizations with shock over time using 2-week intervals. We compared the proportion of hospitalizations with shock in MIS-C and KD patients over time using generalized estimating equations adjusting for hospital clustering and age, with time as a fixed effect. We identified 4868 hospitalizations for MIS-C and 2387 hospitalizations for KD. There was a higher proportion of hospitalizations with shock in MIS-C compared with KD (38.7% vs 5.1%). In our models with time as a fixed effect, we observed a significant decrease in the odds of shock over time in MIS-C patients (odds ratio 0.98, P < .001) but not in KD patients (odds ratio 1.00, P = .062). We provide further evidence that MIS-C is a distinct condition from KD. MIS-C was a source of lower morbidity as the pandemic progressed.

Clinical manifestations and risk factors of shock in children with multisystem inflammatory syndrome

Multisystem inflammatory syndrome in children (MIS-C) is a novel disease associated with COVID-19. The COVID-19 epidemic peaked in May 2022 in Taiwan, and we encountered our first case of MIS-C in late May 2022. We aimed to present patients' clinical manifestations and identify risk factors for shock. We included patients diagnosed with MIS-C at two medical centers from May 2022 to August 2022. We separated those patients into two groups according to whether they experienced shock. We collected demographic, clinical manifestation, and laboratory data of the patients and performed statistical analysis between the two groups. We enrolled 28 patients, including 13 (46%) with shock and 15 (54%) without shock. The median age was 6.4 years (IQR: 1.9-7.5). In single variable analysis, patients with shock tended to be older, had more neurological symptoms, more conjunctivitis and strawberry tongue, lower lymphocyte count, lower platelet counts, and higher C-reactive protein, higher procalcitonin, higher ferritin, and higher D-dimer levels than those without shock. The area under the ROC curve that used procalcitonin to be the risk factor of shock with MIS-C was 0.815 (95% CI 0.644 to 0.987). The cutoff value obtained by ROC analysis of procalcitonin was 1.68ng/mL. With this cutoff, the test characteristics of procalcitonin were as follows: sensitivity 77%, specificity 93%, positive predictive value 91%, negative predictive value 82%. Multivariable analysis revealed that procalcitonin was the only independent risk factor of shock with MIS-C on admission (OR, 26.00, 95% CI, 1.01-668.89). MIS-C patients with high initial procalcitonin levels have higher risks of experiencing shock and may need ICU admission.

Innate immune dysregulation in multisystem inflammatory syndrome in children (MIS-C)

MIS-C is a systemic inflammation disorder with poorly characterised immunopathological mechanisms. We compared changes in the systemic immune response in children with MIS-C (n = 12, 5–13 years) to healthy controls (n = 14, 5–15 years). Analysis was done in whole blood treated with LPS. Expression of CD11b and Toll-like receptor-4 (TLR4) in neutrophils and monocytes were analysed by flow cytometry. Serum cytokines (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-Ira, TNF-α, TNF-β, IFN-Υ, VEGF, EPO and GM-CSF) and mRNA levels of inflammasome molecules (NLRP3, ASC and IL-1β) were evaluated. Subpopulations of lymphocytes (CD3+, CD19+, CD56+, CD4+, CD8+, TCR Vδ1+, TCR Vδ2+) were assessed at basal levels. Absolute counts of neutrophils and NLR were high in children with MIS-C while absolute counts of lymphocytes were low. Children with MIS-C had increased levels of IL-6, IL-10, TNF-β and VEGF serum cytokines at the basal level, and significantly increased TNF-β post-LPS, compared to controls. IL-1RA and EPO decreased at baseline and post-LPS in MIS-C patients compared to controls. The percentage of CD3+ cells, NK cells and Vδ1 was lower while B cells were higher in children with MIS-C than in controls. Dysregulated immune response in children with MIS-C was evident and may be amenable to immunomodulation.

Association between MIS-C and Functional Gastrointestinal Disorders in Children: A Cross-Sectional Study

Abstract Objective Multisystem inflammatory syndrome in children (MIS-C) is a serious complication of coronavirus disease 2019 which causes a hyperinflammatory syndrome that can affect all organ systems. Functional gastrointestinal disorders (FGIDs) are a heterogeneous disease spectrum with unclear etiology. Today, it is known that low-grade inflammation can cause FGIDs. Our aim in this study was to investigate whether there is a higher frequency of FGID in children diagnosed with MIS-C. Methods In this study, 48 pediatric patients diagnosed with MIS-C were evaluated for functional gastrointestinal diseases according to the Rome IV criteria at least 6 months after diagnosis. The control group consisted of 61 pediatric patients without any chronic disease. Results In our study, the overall prevalence of FGIDs was 54.1% (n = 26) in the patient group and 22.9% (n = 14) in the control group. The difference between the groups was statistically significant (p &lt; 0.001). The frequencies of undiagnosed abdominal pain, irritable bowel syndrome, constipation, and dyspepsia were 41.6% (n = 20), 12.5% (n = 6), 8.3% (n = 4), and 6.2% (n = 3) in the patient group, respectively. In the control group, the corresponding rates were 9.8% (n = 6), 3.2% (n = 2), 4.9% (n = 3), and 4.9% (n = 3), respectively. A significant difference was observed between the patient and control groups in terms of functional abdominal pain (p &lt; 0.001). Conclusion The overall frequency of FGIDs and the prevalence of functional abdominal pain were higher in MIS-C patients than in control subjects. The data from this study support the hypothesis that FGIDs are more common in patients diagnosed with MIS-C than in healthy controls.

Multisystem inflammatory syndrome in children (MIS-C) and sepsis differentiation by a clinical and analytical score: MISSEP score

Differential diagnosis between Multisystem Inflammatory Syndrome in Children (MIS-C) and other causes of systemic inflammatory response such as sepsis is complex. The aims were to evaluate the differences between pediatric patients with MIS-C and sepsis and to develop a score to distinguish both entities. This was a retrospective study that compared demographic, clinical, diagnostic, and therapeutic data of pediatric patients with MIS-C (cohort 2020–2022) and sepsis (cohorts 2010–2014 and 2017–2018) admitted to a Pediatric Intensive Care Unit (PICU) of a tertiary care hospital. A diagnostic score was developed with variables that differentiated the two conditions. Twenty-nine patients with MIS-C were identified, who were matched 1:3 with patients with sepsis (n = 87). Patients with MIS-C were older (10 vs. 4 years old), and the majority were male (69%). Clinical characteristics that demonstrated differences were prolonged fever and signs and symptoms affecting skin-mucosa and gastrointestinal system. Leukocytes, PCT, and ferritin were higher in sepsis, while thrombocytopenia, lymphopenia, and elevated fibrinogen and adrenomedullin (biomarker with a role for the detection of invasive infections) were more frequent in MIS-C. MIS-C patients presented greater myocardial dysfunction (p < 0.001). Five criteria were selected and included in the MISSEP score after fitting them into a multivariate logistic regression model: fever > 48 hours (20 points), thrombocytopenia < 150 × 103/µL (6 points), abdominal pain (15 points), conjunctival erythema (11 points), and Vasoactive Inotropic Score (VIS) > 10 (7 points). The cutoff > 25 points allowed to discriminate MIS-C from sepsis with a sensitivity of 0.89 and specificity of 0.95.     Conclusion: MIS-C phenotype overlaps with sepsis. MISSEP score could be useful to distinguish between both entities and direct specific treatment.What is Known:• Differential diagnosis between Multisystem Inflammatory Syndrome in Children (MIS-C) and other causes of systemic inflammatory response such as sepsis is complex.• It is essential to establish an accurate initial diagnosis and early specific treatment in both cases of MIS-C and sepsis to improve the prognosis of these patients.What is New:• Patients with MIS-C are older and have characteristic symptoms of prolonged fever, gastrointestinal symptoms, skin-mucosal involvement, and greater myocardial dysfunction, compared to patients with sepsis.• The use of diagnostic scores, such as the MISSEP score, can be very useful to distinguish between the two entities and help direct specific treatment.

Cardiac biomarkers comparison between acute myocarditis/myopericarditis and multisystem inflammatory syndrome in children

Objectives: Acute myocarditis/myopericarditis is a heterogeneous disorder of unknown origin, the viral etiology leading the first row. There could be also myocardial involvement in multisystem inflammatory syndrome in children (MIS-C). In this study, we aimed to investigate cardiac biomarkers of acute myocarditis/myopericarditis and MIS-C and to compare these parameters between the two diseases. Methods: Patients who are diagnosed with MIS-C, isolated viral myocarditis/myopericarditis at a university hospital from October 2021 to March 2023 are included in this study. Results: There were 38 MIS-C patients and 53 patients with myocarditis/myopericarditis. The mean age was 141.2 ± 38.2 months (4 to 18 years old) in MISC, and 145.8 ± 52.1 months (7 to 18 years old) in myocarditis/myopericarditis. Median troponin I level was 145 ng/L in MIS-C patients and it was 901 ng/L in myocarditis/myopericarditis patients. Creatinine kinase-myocardial band (CK-MB) median was 2.25 ng/mL (0.6-6.3) versus 6.7 ng/mL in MIS-C and myocarditis/myopericarditis, respectively. Pro Brain natriuretic peptide (Pro-BNP) median level was 2714.5 pg/mL (&amp;lt;300) in MIS-C, and it was 294 in patients with myocarditis/myopericarditis. Troponin I, CK-MB was significantly higher in myocarditis/myopericarditis, while Pro-BNP was significantly higher in MIS-C patients (p &amp;lt; 0.05). The separating power of CK-MB, troponin I, and Pro-BNP level was significantly higher in the differential diagnosis of these two group patients (p &amp;lt; 0.001). MIS-C patients with high pro-BNP levels had more prolonged hospitalization and left ventricular function impairment according to myocarditis/myopericarditis. Conclusions: Cardiac biomarkers (CK-MB, troponin I, and Pro-BNP) could be good markers to estimate the course of the diseases.

The Predictive Value of Serum IL-6 in Pediatric Critically Ill Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19

Background Unexplained cases of fatal rapidly spreading viral pneumonia were reported in December 2019 in Wuhan, China. A novel type of coronavirus, SARS-COV-2, was isolated during the examination of patients' samples. By May 2019, the novel coronavirus has been responsible for more than 3 million infections worldwide with a case fatality rate up to 7%. Aim of the Work To evaluate the correlation between serum level of IL-6 and cases of COVID-19 and Multisystem inflammatory syndrome in children (MIS-C) progression and outcome. Patients and Methods This is a cohort study that was conducted at the Pediatric Intensive Care Unut, Ain Shams University. It included 53 patients whose median age was 6 years and ranged between 2-10 years. They were divided into 24 patients (45%) with COVID and 29 patients with MIS-C (55%). Laboratory work up done to both groups include : routine laboratory tests (CBC, CRP, ESR, serum ferritin) and measurement of serum IL-6 using ELISA (Normal values up to 7pg/ml). Results Median serum level of IL-6 was higher albeit insignificant in patients with MIS-C as compared to those with COVID (Median:72.7 pg/ml (range: 20.2-140.5 pg/ml) versus a median of 53 pg/ml (range:17.2-293.2) respectively. Serum IL 6 was significantly positively correlated with CRP, ESR and ferritin in both MIS-C and COVID patients groups (p &amp;lt; 0.05). Among MIS-C patients, the best cut off point of serum IL6 to predict severe course and mortality was &amp;gt;168.2 pg/ml, while among COVID patients, the best cut off level was slightly lower &amp;gt;146 pg/ml. Conclusion Systemic inflammation is a feature of COVID and MIS-C in part reflected by increased serum IL 6 and increased ESR, CRP and Ferritin. Increased serum IL 6 has excellent sensitivity to severe MIS-C and COVID with good specificity. It's low predictive value for mortality suggest it's limited value to predict the outcome in severe cases as indicated by the multiple factors interacting in the disease course.

COVID 19 Related Multisystem Inflammatory Syndrome in Children Admitted to PICU in Ain Shams University Hospitals

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4–6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. Aim of the Work To evaluate the clinical profiles and risk factors for pediatric multisystem inflammatory syndrome in children with COVID-19 admitted to PICU. Patients and Methods This was a cross sectional study conducted on 45 patients admitted to pediatric intensive care unit (PICU) from June 2020 to August 2020, they were diagnosed as MIS-C cases according to CDC definition for MIS-C, using a score to assess hyperinflammatory syndrome, all patients were subjected to the following:(demographic data, clinical signs &amp; symptoms at presentation, sequential organ failure assessment (SOFA) score and laboratory investigations. Results In our study MIS-C patients presented with 100% Kawasaki disease(KD)-like symptoms and 62.2% gastrointestinal symptoms in addition to fever with shock or cardiac dysfunction. Our patients presented with the following vital data: 100% were tachycardic and hypotensive according to centiles, peripheral capillary oxygen saturation (spo2) mean 94.5(2) %, fever of mean 39(0.6) degree celsius and SOFA score mean of 9(2). KD-like features were variably seen in patients (skin rash in 55.6%, conjunctivitis in 46.7% and Cardiovascular abnormalities were seen in 100% e.g. (myocardial dysfunction, valvular regurgitation, coronary dilatation, pericardial effusion and shock). In our patients, 13 patients (28.9%) had comorbid conditions, like (hematologic e.g. ALL, Cardiac e.g. ASD&amp;VSD, Endocrinologic e.g. Diabetes mellitus), 4 of them died revealing comorbidities as a cause of higher mortality with significant p value (0.028). 39 patients (86.7%) were discharged and 6 patients (13.3%) died. Conclusion MIS-C is a hyper-infammatory syndrome affecting multiple organs and is triggered by SARS-CoV-2 infection. It is usually seen 2–4 weeks following infection. comorbidities significantly affected the short term outcome of the disease.