Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.
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ABSTRACT:
SUBMITTER: Channon-Wells S
PROVIDER: S-EPMC9949883 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.
Channon-Wells Samuel S Vito Ortensia O McArdle Andrew J AJ Seaby Eleanor G EG Patel Harsita H Shah Priyen P Pazukhina Ekaterina E Wilson Clare C Broderick Claire C D'Souza Giselle G Keren Ilana I Nijman Ruud G RG Tremoulet Adriana A Munblit Daniel D Ulloa-Gutierrez Rolando R Carter Michael J MJ Ramnarayan Padmanabhan P De Tisham T Hoggart Clive C Whittaker Elizabeth E Herberg Jethro A JA Kaforou Myrsini M Cunnington Aubrey J AJ Blyuss Oleg O Levin Michael M
The Lancet. Rheumatology 20230214 4
<h4>Background</h4>Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments.<h4>Methods</h4>The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-w ...[more]
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Project description:ImportanceMinimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C).ObjectivesTo evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C.Design, setting, and participantsThis retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months.ExposuresGlucocorticoid treatment.Main outcomes and measuresMain outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness.ResultsAmong 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91).Conclusions and relevanceIn this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.
| S-EPMC9652757 | biostudies-literature
Project description:Multisystem inflammatory syndrome in Children (MIS-C) occurs in children between two and six weeks following an initial SARS-CoV-2 infection. The mechanism through which a minority of children develop the hyperinflammation characteristic of MIS-C, while others remain well, is unknown. In this study we present an in-depth assessment of the proteome of children before and after SARS-CoV-2 infection, including children with MIS-C. Reassuringly, these data show that there were minimal changes to the circulating proteome in healthy children as result of SARS-CoV2 infection and there was no evidence of continued inflammation following SARS-CoV-2 infection in children. However, activation of pro-inflammatory pathways and raised circulating markers of myocardial and vascular damage were found to be significantly associated with MIS-C. Our findings have been verified in silico using publicly available proteomic datasets and hence several promising candidate biomarker proteins for diagnosis of MIS-C are identified and described herein.
2025-08-25 | PXD051939 | Pride
Project description:BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a severe disease with an unpredictable course and a substantial risk of cardiogenic shock. Our objectives were to (a) compare MIS-C phenotypes across the COVID-19 pandemic, (b) identify features associated with intensive care need and treatment with biologic agents.MethodsYouth aged 0-18 years, fulfilling the World Health Organization case definition of MIS-C, and admitted to the Alberta Children's Hospital during the first four waves of the COVID-19 pandemic (May 2020-December 2021) were included in this cohort study. Demographic, clinical, biochemical, imaging, and treatment data were captured.ResultsFifty-seven MIS-C patients (median age 6 years, range 0-17) were included. Thirty patients (53%) required intensive care. Patients in the third or fourth wave (indicated as phase 2 of the pandemic) presented with higher peak ferritin (µg/l, median (IQR) = 1134 (409-1806) vs. 370 (249-629), P = 0.001), NT-proBNP (ng/l, median (IQR) = 12,217 (3013-27,161) vs. 3213 (1216-8483), P = 0.02) and D-dimer (mg/l, median (IQR) = 4.81 (2.24-5.37) vs. 2.01 (1.27-3.34), P = 0.004) levels, and higher prevalence of liver enzyme abnormalities (n(%) = 17 (68) vs. 11 (34), P = 0.02), hypoalbuminemia (n(%) = 24 (100) vs. 25 (81), P = 0.03) and thrombocytopenia (n(%) 18 (72) vs. 11 (34), P = 0.007) compared to patients in the first two waves (phase 1). These patients had a higher need of non-invasive/mechanical ventilation (n(%) 4 (16) vs. 0 (0), P = 0.03). Unsupervised clustering analyses classified 47% of the patients in the correct wave and 74% in the correct phase of the pandemic. NT-proBNP was the only significant contributor to the need for intensive care in all applied multivariate regression models. Treatment with biologic agents was significantly associated with peak CRP (mg/l (median, IQR = 240.9 (132.9-319.4) vs. 155.8 (101.0-200.7), P = 0.02) and ferritin levels (µg/l, median (IQR) = 1380 (509-1753) vs. 473 (280-296)).ConclusionsMIS-C patients in a later stage of the pandemic displayed a more severe phenotype, reflecting the impact of distinct SARS-CoV-2 variants. NT-proBNP emerged as the most crucial feature associated with intensive care need, underscoring the importance of monitoring.
| S-EPMC10092941 | biostudies-literature
Project description:In a subset of children and adolescents, SARS-CoV-2 infection leads to multisystem inflammatory syndrome in children (MIS-C), a severe hyperinflammatory shock occurring 4-8 weeks post-infection. MIS-C is characterized by a specific expansion of TCRVβ21.3+ T-cells and systemic hyperinflammation, with an unclear pathogenesis. Here, we show that acute MIS-C exhibits impaired reactivation of virus-specific memory T cells due to elevated TGF-β levels, mirroring severe COVID-19 in adults. Functionally, the impaired T-cell cytotoxicity is accompanied by TGF-β-response signatures and reduced antigen-presentation capabilities of monocytes, reversible by TGF-β blockade. MIS-C TCRVβ21.3+ T cells resemble Epstein-Barr Virus (EBV)-reactive T cells, displaying enhanced capability in eliminating EBV-infected B cells. Clinically, active MIS-C correlates with TGF-β-induced defects in T-cell cytotoxicity, elevated EBV seroprevalence, and EBV-reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, where reduced T-cell cytotoxicity induced by SARS-CoV-2-triggered TGF-β overproduction leads to EBV-reactivation and contributes to hyperinflammation.
2024-12-30 | GSE254179 | GEO
Project description:While fewer cases of severe Coronavirus Disease 2019 (COVID-19) are reported globally in children, a small proportion of SARS-CoV-2 infected children develop a novel pediatric febrile entity called multisystem inflammatory syndrome in children (MIS-C) that develops 2 to 5 weeks after initial SARS-CoV-2 exposure. MIS-C primarily effects male children and children of Hispanic or black descent. MIS-C manifests as a severe and uncontrolled inflammatory response with multiorgan involvement. A hyperinflammatory state is evidenced by clinical makers of inflammation including high levels of C-reactive protein (CRP), ferritin, and D-dimers, and an increased expression of pro-inflammatory cytokines. Children often present with persistent fever, severe gastrointestinal symptoms, cardiovascular manifestations, respiratory symptoms and neurological symptoms6-11,13. Cardiovascular manifestations include hypotension, shock, cardiac dysfunction, myocarditis and pericardial effusion. In the united states, admission to the intensive care unit occurs in approximately 58% of cases. To understand disease pathogenesis of MIS-C and proteins associated with the severe form of disease we performed proteomics analysis of serum or plasma samples. We collected serum from healthy children (SARS-CoV-2 negative, n=20), mild MIS-C (non-ICU, n=5) and severe MIS-C (ICU, n = 20) patients. MIS-C definition and diagnosis was performed according to CDC guidelines. Healthy adult serum (n = 4) was also used for reference ranges quality control and we obtained plasma samples from Kawasaki Disease (KD; n=7) patients that were recruited before the Coronavirus Disease 2019 (COVID-19) pandemic.
2021-09-29 | PXD025462 | Pride
Project description:BackgroundEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.MethodsWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.ResultsData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.ConclusionsWe found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).
| S-EPMC8220965 | biostudies-literature
Project description:BackgroundWe identified patient characteristics associated with an increased risk of developing MIS-C.MethodsWe conducted a longitudinal cohort study of 1,195,327 patients aged 0-19 years between 2006 and 2021, including the first two waves of the pandemic (February 25-August 22, 2020 and August 23, 2020-March 31, 2021). Exposures included prepandemic morbidity, birth outcomes, and family history of maternal disorders. Outcomes included MIS-C, Kawasaki disease, and other Covid-19 complications during the pandemic. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for the association between patient exposures and these outcomes using log-binomial regression models adjusted for potential confounders.ResultsAmong 1,195,327 children, 84 developed MIS-C, 107 Kawasaki disease, and 330 other Covid-19 complications during the first year of the pandemic. Prepandemic hospitalizations for metabolic disorders (RR 11.3, 95% CI 5.61-22.6), atopic conditions (RR 3.34, 95% CI 1.60-6.97), and cancer (RR 8.11, 95% CI 1.13-58.3) were strongly associated with the risk of MIS-C, compared with no exposure. These same exposures were also associated with Kawasaki disease and other Covid-19 complications. However, birth characteristics and history of maternal morbidity were not associated with MIS-C development.ConclusionsChildren with pre-existing morbidity have a considerably elevated risk of MIS-C.ImpactMorbidities that predispose children to multisystem inflammatory syndrome (MIS-C) are unclear. In this study, prepandemic hospitalizations for metabolic disorders, atopic conditions, and cancer were associated with an elevated risk of MIS-C. Birth characteristics and family history of maternal morbidity were not, however, associated with MIS-C. Pediatric morbidities may play a greater role in MIS-C onset than maternal or perinatal characteristics, and may help clinicians better recognize children at risk for this complication.
| S-EPMC10191400 | biostudies-literature
Project description:BackgroundAs a first-line therapeutic option for multisystem inflammatory syndrome in children (MIS-C) with surging demand, intravenous immunoglobulin (IVIG) is associated with escalating costs and supply shortages, particularly in low-income and middle-income countries. This study compares the effectiveness of methylprednisolone alone versus IVIG combined with methylprednisolone for managing MIS-C.MethodsWe conducted a retrospective cohort study from January 2022 to June 2023 at Vietnam National Children's Hospital. We used propensity score matching to compare the short-term outcomes based on immunomodulatory therapy with methylprednisolone alone or IVIG plus methylprednisolone.ResultsWe included 391 patients, comprising 255 boys and 136 girls, who fulfilled the MIS-C case definition of the US Centers for Disease Control and Prevention. Most patients (80.8%) received intravenous methylprednisolone monotherapy, and 19.2% were administered IVIG in addition to methylprednisolone. In general, the laboratory values indicative of hyperinflammatory and hyperthrombotic states displayed significant early response within 2-3 days after initial treatment, including white cell count (SE=1.77, p<0.001), NEU (SE=0.76, p=0.03), C reactive protein (SE=-46.51, p<0.001), PLT (SE=38.05, p=0.002), fibrinogen (SE=-0.37, p=0.002), d-dimer (SE=-849.8, p=0.02)); while subsequent improvement in cardiac markers was also observed, with pro-B-type natriuretic peptide (SE=-165.2, p<0.001) on day 5 and troponin I (SE=-0.05, p=0.004) on day 7. After propensity score weighting, there were 41 patients in each treatment group. Notably, there were no significant differences in the incidence of cardiac events between treatment groups regarding left ventricular dysfunction and coronary artery dilation or aneurysms (10.3% vs 20.7%, p=0.074 and 63.4% vs 56.1%, p=0.653, respectively). While the median paediatric intensive care unit length of stay (LOS) and hospital LOS were slightly lengthier in the IVIG and methylprednisolone group compared with those of the methylprednisolone group, these differences were not statistically significant ((5 vs 4, p=0.782) and (9 vs 7, p=0.725), respectively).ConclusionsInitial treatment with methylprednisolone monotherapy appears not inferior in effectiveness to adjunctive IVIG plus methylprednisolone in MIS-C. Further investigations in randomised controlled trials deserve to be undergone to clarify if IVIG-sparing glucocorticoids are a viable option for achieving favourable outcomes in MIS-C, particularly in resource-limited settings with barriers approaching IVIG therapy.
| S-EPMC11883827 | biostudies-literature
Project description:Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.
| S-EPMC11324515 | biostudies-literature
Project description:BackgroundUnderstanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome.MethodsWe conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms.ResultsWe report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).ConclusionsMultisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).
| S-EPMC7346765 | biostudies-literature