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Open accessJournal ArticleDOI: 10.1001/JAMA.2021.0694

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

02 Mar 2021-JAMA (American Medical Association)-Vol. 325, Iss: 9, pp 855-864
Abstract: Importance Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown Objective To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C Design, Setting, and Participants Retrospective cohort study drawn from a national surveillance system with propensity score–matched analysis All cases with suspected MIS-C were reported to the French National Public Health Agency Confirmed MIS-C cases fulfilling the World Health Organization definition were included The study started on April 1, 2020, and follow-up ended on January 6, 2021 Exposures IVIG and methylprednisolone vs IVIG alone Main Outcomes and Measures The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit The primary analysis involved propensity score matching with a minimum caliper of 01 Results Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 86 years [interquartile range, 47 to 121]) Five children did not receive either treatment Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, −028 [95% CI, −048 to −008]; odds ratio [OR], 025 [95% CI, 009 to 070];P = 008) IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, −022 [95% CI, −040 to −004]; OR, 019 [95% CI, 006 to 061];P = 004), hemodynamic support (absolute risk difference, −017 [95% CI, −034 to −0004]; OR, 021 [95% CI, 006 to 076]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, −018 [95% CI, −035 to −001]; OR, 020 [95% CI, 006 to 066]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, −24 [95% CI, −40 to −07]) Conclusions and Relevance Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course Study interpretation is limited by the observational design

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Topics: Methylprednisolone (52%), Lower risk (51%), Interquartile range (50%)
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70 results found


Open accessJournal ArticleDOI: 10.1056/NEJMOA2102968
Andrew J McArdle1, Ortensia Vito1, Harsita Patel1, Eleanor G. Seaby1  +15 moreInstitutions (1)
Abstract: BACKGROUND Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS We 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. RESULTS Data 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. CONCLUSIONS We 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.

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35 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2102605
Mary Beth F. Son1, Nancy Murray2, Kevin G. Friedman3, Cameron C. Young4  +39 moreInstitutions (20)
Abstract: Background The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods We analyzed surve...

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30 Citations


Open accessJournal ArticleDOI: 10.1136/BMJ.N385
01 Mar 2021-BMJ
Abstract: ### What you need to know The most common symptoms in children with acute SARS-CoV-2 infection (covid-19 disease) are fever and cough. Other symptoms may include sore throat, rhinorrhoea, or congestion, myalgias, headache, fatigue, and gastrointestinal symptoms including nausea, vomiting, or diarrhoea. The range of symptom prevalence is reported from three large meta-analyses, one with 131 studies and 7780 paediatric patients,1 the second with 28 studies and 1614 patients,2 and the third with 46 studies and 551 patients3 and summarised in table 1. Though children have a similar distribution of initial symptoms as compared with adults, children are more likely to have mild, self-resolving symptoms without progression to the lower pulmonary disease that necessitates hospitalisation.4 Dermatological manifestations in children with mild disease are uncommon: acute infection has at times been associated with a maculopapular exanthem, but the pseudo chilblain lesions or “covid toes” seen in adults are rare.56 Although assessing the prevalence of loss of taste or smell among children may be challenging (especially when children …

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Topics: Exanthem (56%), Sore throat (55%)

25 Citations


Open accessJournal ArticleDOI: 10.1172/JCI149633
Lael M. Yonker1, Tal Gilboa1, Tal Gilboa2, Tal Gilboa3  +46 moreInstitutions (6)
Abstract: BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.

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Topics: Zonulin (64%), Intestinal permeability (58%), Systemic inflammatory response syndrome (51%) ... read more

22 Citations


Open accessJournal ArticleDOI: 10.1084/JEM.20210446
Abstract: Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

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16 Citations


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31 results found


Open accessJournal ArticleDOI: 10.1001/JAMA.2020.2648
Zunyou Wu1, Jennifer M. McGoogan1Institutions (1)
07 Apr 2020-JAMA
Abstract: Background: Hospitalised COVID-19 patients are frequently elderly subjects with co-morbidities receiving polypharmacy, all of which are known risk factors for d

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Topics: Outbreak (56%)

10,464 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2021436
Abstract: BackgroundCoronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.MethodsIn this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment.ResultsA total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).ConclusionsIn patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)

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Topics: Lung injury (55%), Mechanical ventilation (52%), Randomized controlled trial (52%) ... read more

4,501 Citations


Open accessJournal ArticleDOI: 10.1161/CIR.0000000000000484
25 Apr 2017-Circulation
Abstract: Background: Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acqui...

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Topics: Kawasaki disease (58%)

1,387 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2021680
Abstract: Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19)...

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1,034 Citations


Open accessJournal ArticleDOI: 10.1001/JAMA.2020.17023
Sterne Jac.1, Srinivas Murthy2, Janet V. Diaz3, Arthur S. Slutsky4  +38 moreInstitutions (20)
02 Sep 2020-JAMA
Abstract: Importance Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using theI2statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios. Exposures Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82];P Conclusions and Relevance In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

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Topics: Randomized controlled trial (60%), Clinical trial (56%), Relative risk (54%) ... read more

961 Citations


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